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Now and Then Above 2001 graduates Shannon McElearney MD Joanna Oda MD and Lineo Thahane M D from lefl The School of Medicine conferred 122 degrees on May 18 102 students received the MD degree 14 received the MDPhD degree and six received the MDI MA degree 8elow Reunion 2001 brought together 1986 classmates Maggie McCracken MD Alison Whelan MD associate dean for medical student education and Michelle 8utzer Ruby MD from left

OUTLOOK Volume XXXVIII Number 2 EDITOR HOLLY EOMISTON CONTACTS Summer 2001 (lSSN 1042-2897) is published quarterly by the Office of

ART DIRECTOR ERIC YOUNG Phone 314286-0100 FAX 314286-0199

Medical Public Affairs Washington PHOTOGRAPHER BOB BOSTON e-mail edmistonh msnoteswustledu University School of Medicine Campus Box 8508 4444 Forest Park Ave CIRCULATION KATHI LAW

Periodical postage paid at St Louis MO POSTMASTER Send address changes to

StLouis MO 63108 (C) 2001 EXECUTIVE STEVE KOHLER Circulation Outlook Campus Box 8508

DIRECTOR 4444 Forest Park Ave St Louis MO 63108 outlook wustledu

hington University ferred-Payment

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See page 36

UIIOO Washington University School of Medicine VOLUME XXXVIIImiddot NUMBER 2 bull SUMMER 2001

COVER William G Powderly MO holds a colorful

assortment of pills which in various combinations make

up the cocktail the therapy which has proven to be

a lifeline for many people infected with HIV (green

model) He and his colleagues at the School of Medicines

AIDS Clinical Trials Unit (ACTU) help patients manage

the disease while holding out hope for better treatments

The potent drug mixture allows people to live longer and

healthier lives yet its long-term consequences are just

beginning to be understood Examining the cocktails

powerful effect on the body is becoming a focus of AIDS

research For more on this story please turn to page 12

DEPARTMENTS

Pulse

Student Stage

Alumni amp Development 26 Profiles

29 Reunion 2001

34 Class Notes

17 The enemy within

FEATURES

I Can See Clearly Now BY CANDACE OCONNOR

An exci ting new therapy aJlows some older adults with age-related eye disease to regain vision and independence

The Cocktail Conundrum BY GILA Z RECKESS

The much-lauded drug cocktail enables persons with A1DS to live longer healthier lives-but at what cost

The Immune System vs Tumors BY GILA Z RECKESS

Linking immunology and oncology researchers find the immune system plays a role in tumor formation

Smile Doctor BY DAVID LINZEE

Providing pediatric dentistry for specia l-needs kids is a prioriry and a pleasure for one faculry member

26 Surgeon and urologist Richard A Blath MD with third-year medical student Caitlin Aveyard

US News ampWorld Report

rankings of medical schools

and their programs

Academy elects Gordon as member JEFFREY r GO RDON MD the Alumni Professor

and h ead of molecular biology and pharmacology

was one of 72 new members elected to the National

Academy of Sciences on May 1 200 1 Election to the

academy is considered one of the highes t honors that

st

~~l1~~r ~~l~~riyi~y~

1st

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3Q~ellP~ti()rl~It~r~py(n)

4th Overall(tie)

4 th

5M~~~~ ~ ~gy

th Internal medicine

5th Neurosciences (t ic)

7th Pediatrics

th

98~~~~~~~gy~~~~~gy ~t~~~

th Genetics

10t~omens health ()

10th Drugalcohol abuse treatn1ent (tic)

11~eriatries(oJ

12~lDs( )12th Health services

administration (tie)

Oenotes 2001 ranking all other active rankings computed in 1999 or 2000

2 Pulse

can be bestowed on an

American scien tist or

engineer and its members

are chosen in recognition

of their distinguished and

con tinuing achievements

in original research

Gordon is known for his

resea rch on gastro intestinal

development and how gut Jeffrey I Gordon VI D

bac teria affec t normal intesshy

tinal function and pred ilection to certain diseases His

research may help scientists understand such commo n

human diseases as inflammatory bowel di sease irritable

bowel syndrome and stomach ulcers

In addition Gordons lab has studied an enzyme

N-myristoyltransferase that affec ts the funct ions of

m any cellular proteins and is requ ired for the survival

of fun gi that cause systemic infections in humans with

compromised immune sys tems

Gordon also is director of the Divi sio n of Biology

and Biomedica l Sciences wh ich oversees all PhD and

MDPhD students in the biological sciences and has

mentored more than 60 young researchers

Boxerman assumes leadership of HAP STUART B BOXERMAN DSC has been named

director of the Health Administration Program at the

School of Medicine He had been serving as interim

director of the program since July 2000 followi ng the

re tirement of James O Hepner PhD

Boxerman ea rned three degrees from Washington

Unive rsiry Two were in engineering-a bachelors degree

in 1963 and a masters degree in 1965 In 1970 he was

awarded his doctorate in applied mathematics and

computer sCience

The Health Ad ministrati on Program founded in

1946 provides its students with a firm foundation in

management integrated with a solid understanding of

the health care field and its current delivery systems

Summer 2001 Outlook

Gelberman named AAOS president RICHARD H GELBERMAN MD the Fred C Reynolds

Professor and head of orthopaedic surgery recently became

presidenc of the 25500-member American Academy of

Orchopaedic SurgelY (AAOS) at its 68th annual meeting

and scientific sess ions in San Francisco CA

A mem ber of the academy since 1981 Gelberman

h as served on more than a dozen of its committees and

task fo rces Most recently he had been one of the organishyza tions vice presidents As president he plans to initiate

a new program designed to improve musculoskeletal care

for the public through better education for doctors

Gelberman also is chief of hand and wrist surgery

and director of the hand and upper extremity fellowship

traini ng program at the School of Medicine and is

orthopaedic-surgeon-in-chief at Barnes-Jewish and

St Louis Childrens hospitals

H e has had support from

the N ational Institutes of

H ealth for his research on

dense regular connective tisshy

sue since 1976 He also has

research interests in radius

fractures ca rpal instabili ty

and nerve injuries

Gelberman is the author

Richard H Gelberman MD of more than 200 scientific man uscripts and has received

many awards for his research He has served on the editoshy

rial boards of several medical publications and currently

serves as a reviewer for the Journal of Bone and Joint Surger)1 and the Journal ofOrthopaedic Research

The AAOS is a no t-for-profit organization that

provides education programs for orthopaedic surgeons

allied health professionals and the public

NEUROLOGY

Mild cognitive impairment appears to be AlzheimerS disease OST PEOPLE DIAGNOSED with mild

cognitive impairment (Mel) evenrualJy

develop Alzheimers disease researchers with

the School of Medicines Memory and Aging

Project (MAP) have found The results suggest that Mel

characterized by minor memory loss is an early stage of

Alzheimers rather than a separate disorder

that the subtle signs of memory loss might indicate the

onset of Alzheimers disease

The volunteers were reassessed annually for up to

95 years After five years Alzheimer symptoms had

developed in 68 percent of the healthy volunteers

199 percent of the individuals in the uncertain MCl

group 357 percent of those in the suspicious group and

We were surprised to find that an 605 percent of those in the fairly

unexplained memory deficit that is curshy confident group By 95 years all of

rendy called MCl almost always turns the volunteers with the most severe

out to be early Alzheimers says John form ofrvlCl had developed the

C Morris MD Harvey A and clinical symptoms of Alzheimers

Dorismae H acker Friedman Professor Forry-two participants died before

of Neurology director of MAP and the end of the srudy and donated

co-director of the Alzheimers Disease their brains for postmortem analysis

Research Center He is first author of a the only way to diagnose Alzheimers

paper on the subject that appeared in disease with complete accuracy

the March issue ofArchives ofNeurology Autopsies of 25 volunteers who origishy

nally were diagnosed with MCIResearchers examined 404 people

who had either mild memory loss or no memory probshy

lems and who volunteered for annual memory assessshy

ments at MAP between July 1990 and June 1997 The

227 individuals with MCI were placed into one of three

categories fairly confident suspicious and uncertain The

categories reAected the researchers degree of confidence

Outlook Summer 2001

confirmed that 21 had Alzheimers disease

Morris points out that these results are based on a

select group of individuals who volunteered for memory

research Even with that caveat the findings are impresshy

sive he says Earlier diagnosis will help scientists develop

more etTective therapies for early intervention

Pulse 3

The mission of FASEBTeitelbaum is FASER president-elect is ro en hance che abili ry of

STEVEN L TEITELBAUM MD has been selected as biomedical and life sciemiscs

the nexc presidenr-elect of the Federation of American ro improve through cheir

Sociecies for Experimencal Biology (FASEB) effeccive research the healch wellshy

July 1 2001 FASEB is che largest coaJicion of biomedical being and productivity of

research associations in che United States represeming all people The organization

21 sociecies wich more chan 60000 members serves the imerests of these

Teicelbaum who is che Wilma and Roswell Messing sciemists particularly in

Professor of Pathology will serve as che groups president areas related to publ ic policy

in 2002-2003 Also a pathologist ac Barnes-Jewish The group also facilitaces coalicion activi ties among

Hospital and Sc Louis Shriners HospitaJ Teitelbaum member societies and di sseminaces information on

sets a primary goal in his new role to promoce federal biological research through scientific conferences and

funding of biomedical and life sciences research publications

PHARMACOGENETICS

Drug resistance found to vary by ethnicity

Steven l Teitelbaum MD

Aenetic mutation affecting resistance to chemotherapy occurs more freshyquently in some ethnic groups than

in others according to a new study Researchers found that African and

African-American populations included more individuals with the drug-resistant gene than Caucasian or Asian populashytions This might help explain why some people of African descent respond poorly to chemotherapy The research was presented March 25 2000 at the annual meeting of the American Association for Cancer Research in New Orleans

We now know that the genetic influence on drug resistance is not the same throughout the whole populashytion says Howard L McLeod PharmO associate professor of medicine of pharshymacology and molecular biology and of genetics Because of this work we can try to solve the problem

McLeod who led the international team of researchers from his previous position at the University of Aberdeen in the United Kingdom specializes in pharshymacogenetics an emerging research field

Margaret-Mary Ameyaw MO PhD of the University of Aberdeen is the studys first author and will join the Washington University faculty later this year

The mutation studied by McLeod and his colleagues changes production of a protein called P-glycoprotein or PGP a molecular pump that rids cells of drugs When working correctly PGP pumps chemotherapeutic drugs out of tumors allowing the tumor cells to survive This

response is known as drug resistance The genetic mutation means the PGP pump stops working allowing drugs to enter and kill tumor cells

Working with collaborators in five countries McLeod and his colleagues did DNA tests on blood samples from 1280

people from 10 ethnic populations They found that some populations were sigshy

nificantly more likely than others to contain the mutation The groups of African descent-Ghanaian Kenyan African American and Sudaneseshyhad the mutation significantly less

frequently than Caucasian and Asian populations tested

Because lack of the mutation is associated with higher expression

of PGP and thus higher drug resistance these findings mean that physicians may soon have the necessary tools for individushyalizing therapy especially for people of African heritage Extreme interventions such as gene therapy would not be necessary because an existing medication that chemically inhibits the PGP protein could be given to people found to overexpress PG P

4 Pulse Summer 200 I Outlook

Students faculty receive Academic Womens Network 2001 awards THREE STUDENTS AND TWO PROFESSORS

recently were recognized for their achievements by the

universitys Academic Womens Network (AWN)

Each year the AWN recognizes graduating students

in either the MD or PhD programs at the medical

school based upon their demonstrated outstanding leadshy

ership in service ro or advancement of women within the

community This years Student Leadership Awards went

to Leah Bernstein PhD Emily Cronbach MD and

Alison Stuebe MD

Bernstein published two I1rst-author publications

and contributed ro a third during her graduate work in

neuroscience Her thesis project focused on the localizashy

tion and regulation of the so-called RGS proteins or

Regularors of G protein Signaling Additionally she has

been active in neuroscience education and in student

government

Cronbach is a summa cum laude graduate of

San Francisco State with a bachelors degree in 111m

Prior ro entering medical school she worked on several

documentaries related to teenagers and HIV She was the

co-organizer of the Reproductive Options Education

program a forum for debate on ethical issues in reproshy

ductive health and she served as co-coordinator of the

student chapter of the American Medical Womens

Association (AMWA) through which she developed a

fourth-year elective in outpatient womens health She

was selected for Alpha Omega Alpha the national

medical honor society

Stuebe is a summa cum laude graduate of Duke

University who came to Washington Universiry after

a st int as producer for the New York Times online site

on womens health She was awarded the School of

Medicines Mr and Mrs Spencer T Olin Fellowship for

Women and also was selected for Alpha Omega Alpha

Stuebe was instrumental in creating the School of

Medicines career counseling web site which she preshy

sented at the 1999 American Association of Medical

Colleges (AAMC) national meeting She was active as

co-coordinator of the student chapter of AMWA and

served on the groups national web site task force

The AWN presented its 2001 Mentor Awards to

twO faculty members Linda B Cotder PhD and

Herberr W Virgin IV MD PhD

Cotder professor of psychiatry (epidemiology)

joined the Washington University faculty in 1990 She

received her MPH from Boston University School of

Public Health in 1980 and her PhD from Washington

University in 1987 Virgin is an associate professor in medicine in

molecular microbiology and in pathology and immunolshy

ogy He received his MDPhD from Harvard University

and joined the Washington University faculty in 1991

Outstanding Student Researcher Third-year medical student Clint Walker (center) receives the Alpha Omega Alpha (AOA) 2001 Student Research Fellowship Award from Scot G Hickman M0 (left) professor of medicine and president of the School of Medicines AOA chapter Walker was awarded $3000 in support of his research on peripheral nerves His advisers on the project are fellow John Winograd MD (right) and Susan E Mackinnon MD professor and head of the division of plastic and reconstructive surgery

Outlook Su m mer 2001 Pulse 5

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

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8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

hington University ferred-Payment

itable Gift Annuity

See page 36

UIIOO Washington University School of Medicine VOLUME XXXVIIImiddot NUMBER 2 bull SUMMER 2001

COVER William G Powderly MO holds a colorful

assortment of pills which in various combinations make

up the cocktail the therapy which has proven to be

a lifeline for many people infected with HIV (green

model) He and his colleagues at the School of Medicines

AIDS Clinical Trials Unit (ACTU) help patients manage

the disease while holding out hope for better treatments

The potent drug mixture allows people to live longer and

healthier lives yet its long-term consequences are just

beginning to be understood Examining the cocktails

powerful effect on the body is becoming a focus of AIDS

research For more on this story please turn to page 12

DEPARTMENTS

Pulse

Student Stage

Alumni amp Development 26 Profiles

29 Reunion 2001

34 Class Notes

17 The enemy within

FEATURES

I Can See Clearly Now BY CANDACE OCONNOR

An exci ting new therapy aJlows some older adults with age-related eye disease to regain vision and independence

The Cocktail Conundrum BY GILA Z RECKESS

The much-lauded drug cocktail enables persons with A1DS to live longer healthier lives-but at what cost

The Immune System vs Tumors BY GILA Z RECKESS

Linking immunology and oncology researchers find the immune system plays a role in tumor formation

Smile Doctor BY DAVID LINZEE

Providing pediatric dentistry for specia l-needs kids is a prioriry and a pleasure for one faculry member

26 Surgeon and urologist Richard A Blath MD with third-year medical student Caitlin Aveyard

US News ampWorld Report

rankings of medical schools

and their programs

Academy elects Gordon as member JEFFREY r GO RDON MD the Alumni Professor

and h ead of molecular biology and pharmacology

was one of 72 new members elected to the National

Academy of Sciences on May 1 200 1 Election to the

academy is considered one of the highes t honors that

st

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1st

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3Q~ellP~ti()rl~It~r~py(n)

4th Overall(tie)

4 th

5M~~~~ ~ ~gy

th Internal medicine

5th Neurosciences (t ic)

7th Pediatrics

th

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th Genetics

10t~omens health ()

10th Drugalcohol abuse treatn1ent (tic)

11~eriatries(oJ

12~lDs( )12th Health services

administration (tie)

Oenotes 2001 ranking all other active rankings computed in 1999 or 2000

2 Pulse

can be bestowed on an

American scien tist or

engineer and its members

are chosen in recognition

of their distinguished and

con tinuing achievements

in original research

Gordon is known for his

resea rch on gastro intestinal

development and how gut Jeffrey I Gordon VI D

bac teria affec t normal intesshy

tinal function and pred ilection to certain diseases His

research may help scientists understand such commo n

human diseases as inflammatory bowel di sease irritable

bowel syndrome and stomach ulcers

In addition Gordons lab has studied an enzyme

N-myristoyltransferase that affec ts the funct ions of

m any cellular proteins and is requ ired for the survival

of fun gi that cause systemic infections in humans with

compromised immune sys tems

Gordon also is director of the Divi sio n of Biology

and Biomedica l Sciences wh ich oversees all PhD and

MDPhD students in the biological sciences and has

mentored more than 60 young researchers

Boxerman assumes leadership of HAP STUART B BOXERMAN DSC has been named

director of the Health Administration Program at the

School of Medicine He had been serving as interim

director of the program since July 2000 followi ng the

re tirement of James O Hepner PhD

Boxerman ea rned three degrees from Washington

Unive rsiry Two were in engineering-a bachelors degree

in 1963 and a masters degree in 1965 In 1970 he was

awarded his doctorate in applied mathematics and

computer sCience

The Health Ad ministrati on Program founded in

1946 provides its students with a firm foundation in

management integrated with a solid understanding of

the health care field and its current delivery systems

Summer 2001 Outlook

Gelberman named AAOS president RICHARD H GELBERMAN MD the Fred C Reynolds

Professor and head of orthopaedic surgery recently became

presidenc of the 25500-member American Academy of

Orchopaedic SurgelY (AAOS) at its 68th annual meeting

and scientific sess ions in San Francisco CA

A mem ber of the academy since 1981 Gelberman

h as served on more than a dozen of its committees and

task fo rces Most recently he had been one of the organishyza tions vice presidents As president he plans to initiate

a new program designed to improve musculoskeletal care

for the public through better education for doctors

Gelberman also is chief of hand and wrist surgery

and director of the hand and upper extremity fellowship

traini ng program at the School of Medicine and is

orthopaedic-surgeon-in-chief at Barnes-Jewish and

St Louis Childrens hospitals

H e has had support from

the N ational Institutes of

H ealth for his research on

dense regular connective tisshy

sue since 1976 He also has

research interests in radius

fractures ca rpal instabili ty

and nerve injuries

Gelberman is the author

Richard H Gelberman MD of more than 200 scientific man uscripts and has received

many awards for his research He has served on the editoshy

rial boards of several medical publications and currently

serves as a reviewer for the Journal of Bone and Joint Surger)1 and the Journal ofOrthopaedic Research

The AAOS is a no t-for-profit organization that

provides education programs for orthopaedic surgeons

allied health professionals and the public

NEUROLOGY

Mild cognitive impairment appears to be AlzheimerS disease OST PEOPLE DIAGNOSED with mild

cognitive impairment (Mel) evenrualJy

develop Alzheimers disease researchers with

the School of Medicines Memory and Aging

Project (MAP) have found The results suggest that Mel

characterized by minor memory loss is an early stage of

Alzheimers rather than a separate disorder

that the subtle signs of memory loss might indicate the

onset of Alzheimers disease

The volunteers were reassessed annually for up to

95 years After five years Alzheimer symptoms had

developed in 68 percent of the healthy volunteers

199 percent of the individuals in the uncertain MCl

group 357 percent of those in the suspicious group and

We were surprised to find that an 605 percent of those in the fairly

unexplained memory deficit that is curshy confident group By 95 years all of

rendy called MCl almost always turns the volunteers with the most severe

out to be early Alzheimers says John form ofrvlCl had developed the

C Morris MD Harvey A and clinical symptoms of Alzheimers

Dorismae H acker Friedman Professor Forry-two participants died before

of Neurology director of MAP and the end of the srudy and donated

co-director of the Alzheimers Disease their brains for postmortem analysis

Research Center He is first author of a the only way to diagnose Alzheimers

paper on the subject that appeared in disease with complete accuracy

the March issue ofArchives ofNeurology Autopsies of 25 volunteers who origishy

nally were diagnosed with MCIResearchers examined 404 people

who had either mild memory loss or no memory probshy

lems and who volunteered for annual memory assessshy

ments at MAP between July 1990 and June 1997 The

227 individuals with MCI were placed into one of three

categories fairly confident suspicious and uncertain The

categories reAected the researchers degree of confidence

Outlook Summer 2001

confirmed that 21 had Alzheimers disease

Morris points out that these results are based on a

select group of individuals who volunteered for memory

research Even with that caveat the findings are impresshy

sive he says Earlier diagnosis will help scientists develop

more etTective therapies for early intervention

Pulse 3

The mission of FASEBTeitelbaum is FASER president-elect is ro en hance che abili ry of

STEVEN L TEITELBAUM MD has been selected as biomedical and life sciemiscs

the nexc presidenr-elect of the Federation of American ro improve through cheir

Sociecies for Experimencal Biology (FASEB) effeccive research the healch wellshy

July 1 2001 FASEB is che largest coaJicion of biomedical being and productivity of

research associations in che United States represeming all people The organization

21 sociecies wich more chan 60000 members serves the imerests of these

Teicelbaum who is che Wilma and Roswell Messing sciemists particularly in

Professor of Pathology will serve as che groups president areas related to publ ic policy

in 2002-2003 Also a pathologist ac Barnes-Jewish The group also facilitaces coalicion activi ties among

Hospital and Sc Louis Shriners HospitaJ Teitelbaum member societies and di sseminaces information on

sets a primary goal in his new role to promoce federal biological research through scientific conferences and

funding of biomedical and life sciences research publications

PHARMACOGENETICS

Drug resistance found to vary by ethnicity

Steven l Teitelbaum MD

Aenetic mutation affecting resistance to chemotherapy occurs more freshyquently in some ethnic groups than

in others according to a new study Researchers found that African and

African-American populations included more individuals with the drug-resistant gene than Caucasian or Asian populashytions This might help explain why some people of African descent respond poorly to chemotherapy The research was presented March 25 2000 at the annual meeting of the American Association for Cancer Research in New Orleans

We now know that the genetic influence on drug resistance is not the same throughout the whole populashytion says Howard L McLeod PharmO associate professor of medicine of pharshymacology and molecular biology and of genetics Because of this work we can try to solve the problem

McLeod who led the international team of researchers from his previous position at the University of Aberdeen in the United Kingdom specializes in pharshymacogenetics an emerging research field

Margaret-Mary Ameyaw MO PhD of the University of Aberdeen is the studys first author and will join the Washington University faculty later this year

The mutation studied by McLeod and his colleagues changes production of a protein called P-glycoprotein or PGP a molecular pump that rids cells of drugs When working correctly PGP pumps chemotherapeutic drugs out of tumors allowing the tumor cells to survive This

response is known as drug resistance The genetic mutation means the PGP pump stops working allowing drugs to enter and kill tumor cells

Working with collaborators in five countries McLeod and his colleagues did DNA tests on blood samples from 1280

people from 10 ethnic populations They found that some populations were sigshy

nificantly more likely than others to contain the mutation The groups of African descent-Ghanaian Kenyan African American and Sudaneseshyhad the mutation significantly less

frequently than Caucasian and Asian populations tested

Because lack of the mutation is associated with higher expression

of PGP and thus higher drug resistance these findings mean that physicians may soon have the necessary tools for individushyalizing therapy especially for people of African heritage Extreme interventions such as gene therapy would not be necessary because an existing medication that chemically inhibits the PGP protein could be given to people found to overexpress PG P

4 Pulse Summer 200 I Outlook

Students faculty receive Academic Womens Network 2001 awards THREE STUDENTS AND TWO PROFESSORS

recently were recognized for their achievements by the

universitys Academic Womens Network (AWN)

Each year the AWN recognizes graduating students

in either the MD or PhD programs at the medical

school based upon their demonstrated outstanding leadshy

ership in service ro or advancement of women within the

community This years Student Leadership Awards went

to Leah Bernstein PhD Emily Cronbach MD and

Alison Stuebe MD

Bernstein published two I1rst-author publications

and contributed ro a third during her graduate work in

neuroscience Her thesis project focused on the localizashy

tion and regulation of the so-called RGS proteins or

Regularors of G protein Signaling Additionally she has

been active in neuroscience education and in student

government

Cronbach is a summa cum laude graduate of

San Francisco State with a bachelors degree in 111m

Prior ro entering medical school she worked on several

documentaries related to teenagers and HIV She was the

co-organizer of the Reproductive Options Education

program a forum for debate on ethical issues in reproshy

ductive health and she served as co-coordinator of the

student chapter of the American Medical Womens

Association (AMWA) through which she developed a

fourth-year elective in outpatient womens health She

was selected for Alpha Omega Alpha the national

medical honor society

Stuebe is a summa cum laude graduate of Duke

University who came to Washington Universiry after

a st int as producer for the New York Times online site

on womens health She was awarded the School of

Medicines Mr and Mrs Spencer T Olin Fellowship for

Women and also was selected for Alpha Omega Alpha

Stuebe was instrumental in creating the School of

Medicines career counseling web site which she preshy

sented at the 1999 American Association of Medical

Colleges (AAMC) national meeting She was active as

co-coordinator of the student chapter of AMWA and

served on the groups national web site task force

The AWN presented its 2001 Mentor Awards to

twO faculty members Linda B Cotder PhD and

Herberr W Virgin IV MD PhD

Cotder professor of psychiatry (epidemiology)

joined the Washington University faculty in 1990 She

received her MPH from Boston University School of

Public Health in 1980 and her PhD from Washington

University in 1987 Virgin is an associate professor in medicine in

molecular microbiology and in pathology and immunolshy

ogy He received his MDPhD from Harvard University

and joined the Washington University faculty in 1991

Outstanding Student Researcher Third-year medical student Clint Walker (center) receives the Alpha Omega Alpha (AOA) 2001 Student Research Fellowship Award from Scot G Hickman M0 (left) professor of medicine and president of the School of Medicines AOA chapter Walker was awarded $3000 in support of his research on peripheral nerves His advisers on the project are fellow John Winograd MD (right) and Susan E Mackinnon MD professor and head of the division of plastic and reconstructive surgery

Outlook Su m mer 2001 Pulse 5

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

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8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

UIIOO Washington University School of Medicine VOLUME XXXVIIImiddot NUMBER 2 bull SUMMER 2001

COVER William G Powderly MO holds a colorful

assortment of pills which in various combinations make

up the cocktail the therapy which has proven to be

a lifeline for many people infected with HIV (green

model) He and his colleagues at the School of Medicines

AIDS Clinical Trials Unit (ACTU) help patients manage

the disease while holding out hope for better treatments

The potent drug mixture allows people to live longer and

healthier lives yet its long-term consequences are just

beginning to be understood Examining the cocktails

powerful effect on the body is becoming a focus of AIDS

research For more on this story please turn to page 12

DEPARTMENTS

Pulse

Student Stage

Alumni amp Development 26 Profiles

29 Reunion 2001

34 Class Notes

17 The enemy within

FEATURES

I Can See Clearly Now BY CANDACE OCONNOR

An exci ting new therapy aJlows some older adults with age-related eye disease to regain vision and independence

The Cocktail Conundrum BY GILA Z RECKESS

The much-lauded drug cocktail enables persons with A1DS to live longer healthier lives-but at what cost

The Immune System vs Tumors BY GILA Z RECKESS

Linking immunology and oncology researchers find the immune system plays a role in tumor formation

Smile Doctor BY DAVID LINZEE

Providing pediatric dentistry for specia l-needs kids is a prioriry and a pleasure for one faculry member

26 Surgeon and urologist Richard A Blath MD with third-year medical student Caitlin Aveyard

US News ampWorld Report

rankings of medical schools

and their programs

Academy elects Gordon as member JEFFREY r GO RDON MD the Alumni Professor

and h ead of molecular biology and pharmacology

was one of 72 new members elected to the National

Academy of Sciences on May 1 200 1 Election to the

academy is considered one of the highes t honors that

st

~~l1~~r ~~l~~riyi~y~

1st

hY~ ~~~~~~~ l~~PY

3Q~ellP~ti()rl~It~r~py(n)

4th Overall(tie)

4 th

5M~~~~ ~ ~gy

th Internal medicine

5th Neurosciences (t ic)

7th Pediatrics

th

98~~~~~~~gy~~~~~gy ~t~~~

th Genetics

10t~omens health ()

10th Drugalcohol abuse treatn1ent (tic)

11~eriatries(oJ

12~lDs( )12th Health services

administration (tie)

Oenotes 2001 ranking all other active rankings computed in 1999 or 2000

2 Pulse

can be bestowed on an

American scien tist or

engineer and its members

are chosen in recognition

of their distinguished and

con tinuing achievements

in original research

Gordon is known for his

resea rch on gastro intestinal

development and how gut Jeffrey I Gordon VI D

bac teria affec t normal intesshy

tinal function and pred ilection to certain diseases His

research may help scientists understand such commo n

human diseases as inflammatory bowel di sease irritable

bowel syndrome and stomach ulcers

In addition Gordons lab has studied an enzyme

N-myristoyltransferase that affec ts the funct ions of

m any cellular proteins and is requ ired for the survival

of fun gi that cause systemic infections in humans with

compromised immune sys tems

Gordon also is director of the Divi sio n of Biology

and Biomedica l Sciences wh ich oversees all PhD and

MDPhD students in the biological sciences and has

mentored more than 60 young researchers

Boxerman assumes leadership of HAP STUART B BOXERMAN DSC has been named

director of the Health Administration Program at the

School of Medicine He had been serving as interim

director of the program since July 2000 followi ng the

re tirement of James O Hepner PhD

Boxerman ea rned three degrees from Washington

Unive rsiry Two were in engineering-a bachelors degree

in 1963 and a masters degree in 1965 In 1970 he was

awarded his doctorate in applied mathematics and

computer sCience

The Health Ad ministrati on Program founded in

1946 provides its students with a firm foundation in

management integrated with a solid understanding of

the health care field and its current delivery systems

Summer 2001 Outlook

Gelberman named AAOS president RICHARD H GELBERMAN MD the Fred C Reynolds

Professor and head of orthopaedic surgery recently became

presidenc of the 25500-member American Academy of

Orchopaedic SurgelY (AAOS) at its 68th annual meeting

and scientific sess ions in San Francisco CA

A mem ber of the academy since 1981 Gelberman

h as served on more than a dozen of its committees and

task fo rces Most recently he had been one of the organishyza tions vice presidents As president he plans to initiate

a new program designed to improve musculoskeletal care

for the public through better education for doctors

Gelberman also is chief of hand and wrist surgery

and director of the hand and upper extremity fellowship

traini ng program at the School of Medicine and is

orthopaedic-surgeon-in-chief at Barnes-Jewish and

St Louis Childrens hospitals

H e has had support from

the N ational Institutes of

H ealth for his research on

dense regular connective tisshy

sue since 1976 He also has

research interests in radius

fractures ca rpal instabili ty

and nerve injuries

Gelberman is the author

Richard H Gelberman MD of more than 200 scientific man uscripts and has received

many awards for his research He has served on the editoshy

rial boards of several medical publications and currently

serves as a reviewer for the Journal of Bone and Joint Surger)1 and the Journal ofOrthopaedic Research

The AAOS is a no t-for-profit organization that

provides education programs for orthopaedic surgeons

allied health professionals and the public

NEUROLOGY

Mild cognitive impairment appears to be AlzheimerS disease OST PEOPLE DIAGNOSED with mild

cognitive impairment (Mel) evenrualJy

develop Alzheimers disease researchers with

the School of Medicines Memory and Aging

Project (MAP) have found The results suggest that Mel

characterized by minor memory loss is an early stage of

Alzheimers rather than a separate disorder

that the subtle signs of memory loss might indicate the

onset of Alzheimers disease

The volunteers were reassessed annually for up to

95 years After five years Alzheimer symptoms had

developed in 68 percent of the healthy volunteers

199 percent of the individuals in the uncertain MCl

group 357 percent of those in the suspicious group and

We were surprised to find that an 605 percent of those in the fairly

unexplained memory deficit that is curshy confident group By 95 years all of

rendy called MCl almost always turns the volunteers with the most severe

out to be early Alzheimers says John form ofrvlCl had developed the

C Morris MD Harvey A and clinical symptoms of Alzheimers

Dorismae H acker Friedman Professor Forry-two participants died before

of Neurology director of MAP and the end of the srudy and donated

co-director of the Alzheimers Disease their brains for postmortem analysis

Research Center He is first author of a the only way to diagnose Alzheimers

paper on the subject that appeared in disease with complete accuracy

the March issue ofArchives ofNeurology Autopsies of 25 volunteers who origishy

nally were diagnosed with MCIResearchers examined 404 people

who had either mild memory loss or no memory probshy

lems and who volunteered for annual memory assessshy

ments at MAP between July 1990 and June 1997 The

227 individuals with MCI were placed into one of three

categories fairly confident suspicious and uncertain The

categories reAected the researchers degree of confidence

Outlook Summer 2001

confirmed that 21 had Alzheimers disease

Morris points out that these results are based on a

select group of individuals who volunteered for memory

research Even with that caveat the findings are impresshy

sive he says Earlier diagnosis will help scientists develop

more etTective therapies for early intervention

Pulse 3

The mission of FASEBTeitelbaum is FASER president-elect is ro en hance che abili ry of

STEVEN L TEITELBAUM MD has been selected as biomedical and life sciemiscs

the nexc presidenr-elect of the Federation of American ro improve through cheir

Sociecies for Experimencal Biology (FASEB) effeccive research the healch wellshy

July 1 2001 FASEB is che largest coaJicion of biomedical being and productivity of

research associations in che United States represeming all people The organization

21 sociecies wich more chan 60000 members serves the imerests of these

Teicelbaum who is che Wilma and Roswell Messing sciemists particularly in

Professor of Pathology will serve as che groups president areas related to publ ic policy

in 2002-2003 Also a pathologist ac Barnes-Jewish The group also facilitaces coalicion activi ties among

Hospital and Sc Louis Shriners HospitaJ Teitelbaum member societies and di sseminaces information on

sets a primary goal in his new role to promoce federal biological research through scientific conferences and

funding of biomedical and life sciences research publications

PHARMACOGENETICS

Drug resistance found to vary by ethnicity

Steven l Teitelbaum MD

Aenetic mutation affecting resistance to chemotherapy occurs more freshyquently in some ethnic groups than

in others according to a new study Researchers found that African and

African-American populations included more individuals with the drug-resistant gene than Caucasian or Asian populashytions This might help explain why some people of African descent respond poorly to chemotherapy The research was presented March 25 2000 at the annual meeting of the American Association for Cancer Research in New Orleans

We now know that the genetic influence on drug resistance is not the same throughout the whole populashytion says Howard L McLeod PharmO associate professor of medicine of pharshymacology and molecular biology and of genetics Because of this work we can try to solve the problem

McLeod who led the international team of researchers from his previous position at the University of Aberdeen in the United Kingdom specializes in pharshymacogenetics an emerging research field

Margaret-Mary Ameyaw MO PhD of the University of Aberdeen is the studys first author and will join the Washington University faculty later this year

The mutation studied by McLeod and his colleagues changes production of a protein called P-glycoprotein or PGP a molecular pump that rids cells of drugs When working correctly PGP pumps chemotherapeutic drugs out of tumors allowing the tumor cells to survive This

response is known as drug resistance The genetic mutation means the PGP pump stops working allowing drugs to enter and kill tumor cells

Working with collaborators in five countries McLeod and his colleagues did DNA tests on blood samples from 1280

people from 10 ethnic populations They found that some populations were sigshy

nificantly more likely than others to contain the mutation The groups of African descent-Ghanaian Kenyan African American and Sudaneseshyhad the mutation significantly less

frequently than Caucasian and Asian populations tested

Because lack of the mutation is associated with higher expression

of PGP and thus higher drug resistance these findings mean that physicians may soon have the necessary tools for individushyalizing therapy especially for people of African heritage Extreme interventions such as gene therapy would not be necessary because an existing medication that chemically inhibits the PGP protein could be given to people found to overexpress PG P

4 Pulse Summer 200 I Outlook

Students faculty receive Academic Womens Network 2001 awards THREE STUDENTS AND TWO PROFESSORS

recently were recognized for their achievements by the

universitys Academic Womens Network (AWN)

Each year the AWN recognizes graduating students

in either the MD or PhD programs at the medical

school based upon their demonstrated outstanding leadshy

ership in service ro or advancement of women within the

community This years Student Leadership Awards went

to Leah Bernstein PhD Emily Cronbach MD and

Alison Stuebe MD

Bernstein published two I1rst-author publications

and contributed ro a third during her graduate work in

neuroscience Her thesis project focused on the localizashy

tion and regulation of the so-called RGS proteins or

Regularors of G protein Signaling Additionally she has

been active in neuroscience education and in student

government

Cronbach is a summa cum laude graduate of

San Francisco State with a bachelors degree in 111m

Prior ro entering medical school she worked on several

documentaries related to teenagers and HIV She was the

co-organizer of the Reproductive Options Education

program a forum for debate on ethical issues in reproshy

ductive health and she served as co-coordinator of the

student chapter of the American Medical Womens

Association (AMWA) through which she developed a

fourth-year elective in outpatient womens health She

was selected for Alpha Omega Alpha the national

medical honor society

Stuebe is a summa cum laude graduate of Duke

University who came to Washington Universiry after

a st int as producer for the New York Times online site

on womens health She was awarded the School of

Medicines Mr and Mrs Spencer T Olin Fellowship for

Women and also was selected for Alpha Omega Alpha

Stuebe was instrumental in creating the School of

Medicines career counseling web site which she preshy

sented at the 1999 American Association of Medical

Colleges (AAMC) national meeting She was active as

co-coordinator of the student chapter of AMWA and

served on the groups national web site task force

The AWN presented its 2001 Mentor Awards to

twO faculty members Linda B Cotder PhD and

Herberr W Virgin IV MD PhD

Cotder professor of psychiatry (epidemiology)

joined the Washington University faculty in 1990 She

received her MPH from Boston University School of

Public Health in 1980 and her PhD from Washington

University in 1987 Virgin is an associate professor in medicine in

molecular microbiology and in pathology and immunolshy

ogy He received his MDPhD from Harvard University

and joined the Washington University faculty in 1991

Outstanding Student Researcher Third-year medical student Clint Walker (center) receives the Alpha Omega Alpha (AOA) 2001 Student Research Fellowship Award from Scot G Hickman M0 (left) professor of medicine and president of the School of Medicines AOA chapter Walker was awarded $3000 in support of his research on peripheral nerves His advisers on the project are fellow John Winograd MD (right) and Susan E Mackinnon MD professor and head of the division of plastic and reconstructive surgery

Outlook Su m mer 2001 Pulse 5

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

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8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

US News ampWorld Report

rankings of medical schools

and their programs

Academy elects Gordon as member JEFFREY r GO RDON MD the Alumni Professor

and h ead of molecular biology and pharmacology

was one of 72 new members elected to the National

Academy of Sciences on May 1 200 1 Election to the

academy is considered one of the highes t honors that

st

~~l1~~r ~~l~~riyi~y~

1st

hY~ ~~~~~~~ l~~PY

3Q~ellP~ti()rl~It~r~py(n)

4th Overall(tie)

4 th

5M~~~~ ~ ~gy

th Internal medicine

5th Neurosciences (t ic)

7th Pediatrics

th

98~~~~~~~gy~~~~~gy ~t~~~

th Genetics

10t~omens health ()

10th Drugalcohol abuse treatn1ent (tic)

11~eriatries(oJ

12~lDs( )12th Health services

administration (tie)

Oenotes 2001 ranking all other active rankings computed in 1999 or 2000

2 Pulse

can be bestowed on an

American scien tist or

engineer and its members

are chosen in recognition

of their distinguished and

con tinuing achievements

in original research

Gordon is known for his

resea rch on gastro intestinal

development and how gut Jeffrey I Gordon VI D

bac teria affec t normal intesshy

tinal function and pred ilection to certain diseases His

research may help scientists understand such commo n

human diseases as inflammatory bowel di sease irritable

bowel syndrome and stomach ulcers

In addition Gordons lab has studied an enzyme

N-myristoyltransferase that affec ts the funct ions of

m any cellular proteins and is requ ired for the survival

of fun gi that cause systemic infections in humans with

compromised immune sys tems

Gordon also is director of the Divi sio n of Biology

and Biomedica l Sciences wh ich oversees all PhD and

MDPhD students in the biological sciences and has

mentored more than 60 young researchers

Boxerman assumes leadership of HAP STUART B BOXERMAN DSC has been named

director of the Health Administration Program at the

School of Medicine He had been serving as interim

director of the program since July 2000 followi ng the

re tirement of James O Hepner PhD

Boxerman ea rned three degrees from Washington

Unive rsiry Two were in engineering-a bachelors degree

in 1963 and a masters degree in 1965 In 1970 he was

awarded his doctorate in applied mathematics and

computer sCience

The Health Ad ministrati on Program founded in

1946 provides its students with a firm foundation in

management integrated with a solid understanding of

the health care field and its current delivery systems

Summer 2001 Outlook

Gelberman named AAOS president RICHARD H GELBERMAN MD the Fred C Reynolds

Professor and head of orthopaedic surgery recently became

presidenc of the 25500-member American Academy of

Orchopaedic SurgelY (AAOS) at its 68th annual meeting

and scientific sess ions in San Francisco CA

A mem ber of the academy since 1981 Gelberman

h as served on more than a dozen of its committees and

task fo rces Most recently he had been one of the organishyza tions vice presidents As president he plans to initiate

a new program designed to improve musculoskeletal care

for the public through better education for doctors

Gelberman also is chief of hand and wrist surgery

and director of the hand and upper extremity fellowship

traini ng program at the School of Medicine and is

orthopaedic-surgeon-in-chief at Barnes-Jewish and

St Louis Childrens hospitals

H e has had support from

the N ational Institutes of

H ealth for his research on

dense regular connective tisshy

sue since 1976 He also has

research interests in radius

fractures ca rpal instabili ty

and nerve injuries

Gelberman is the author

Richard H Gelberman MD of more than 200 scientific man uscripts and has received

many awards for his research He has served on the editoshy

rial boards of several medical publications and currently

serves as a reviewer for the Journal of Bone and Joint Surger)1 and the Journal ofOrthopaedic Research

The AAOS is a no t-for-profit organization that

provides education programs for orthopaedic surgeons

allied health professionals and the public

NEUROLOGY

Mild cognitive impairment appears to be AlzheimerS disease OST PEOPLE DIAGNOSED with mild

cognitive impairment (Mel) evenrualJy

develop Alzheimers disease researchers with

the School of Medicines Memory and Aging

Project (MAP) have found The results suggest that Mel

characterized by minor memory loss is an early stage of

Alzheimers rather than a separate disorder

that the subtle signs of memory loss might indicate the

onset of Alzheimers disease

The volunteers were reassessed annually for up to

95 years After five years Alzheimer symptoms had

developed in 68 percent of the healthy volunteers

199 percent of the individuals in the uncertain MCl

group 357 percent of those in the suspicious group and

We were surprised to find that an 605 percent of those in the fairly

unexplained memory deficit that is curshy confident group By 95 years all of

rendy called MCl almost always turns the volunteers with the most severe

out to be early Alzheimers says John form ofrvlCl had developed the

C Morris MD Harvey A and clinical symptoms of Alzheimers

Dorismae H acker Friedman Professor Forry-two participants died before

of Neurology director of MAP and the end of the srudy and donated

co-director of the Alzheimers Disease their brains for postmortem analysis

Research Center He is first author of a the only way to diagnose Alzheimers

paper on the subject that appeared in disease with complete accuracy

the March issue ofArchives ofNeurology Autopsies of 25 volunteers who origishy

nally were diagnosed with MCIResearchers examined 404 people

who had either mild memory loss or no memory probshy

lems and who volunteered for annual memory assessshy

ments at MAP between July 1990 and June 1997 The

227 individuals with MCI were placed into one of three

categories fairly confident suspicious and uncertain The

categories reAected the researchers degree of confidence

Outlook Summer 2001

confirmed that 21 had Alzheimers disease

Morris points out that these results are based on a

select group of individuals who volunteered for memory

research Even with that caveat the findings are impresshy

sive he says Earlier diagnosis will help scientists develop

more etTective therapies for early intervention

Pulse 3

The mission of FASEBTeitelbaum is FASER president-elect is ro en hance che abili ry of

STEVEN L TEITELBAUM MD has been selected as biomedical and life sciemiscs

the nexc presidenr-elect of the Federation of American ro improve through cheir

Sociecies for Experimencal Biology (FASEB) effeccive research the healch wellshy

July 1 2001 FASEB is che largest coaJicion of biomedical being and productivity of

research associations in che United States represeming all people The organization

21 sociecies wich more chan 60000 members serves the imerests of these

Teicelbaum who is che Wilma and Roswell Messing sciemists particularly in

Professor of Pathology will serve as che groups president areas related to publ ic policy

in 2002-2003 Also a pathologist ac Barnes-Jewish The group also facilitaces coalicion activi ties among

Hospital and Sc Louis Shriners HospitaJ Teitelbaum member societies and di sseminaces information on

sets a primary goal in his new role to promoce federal biological research through scientific conferences and

funding of biomedical and life sciences research publications

PHARMACOGENETICS

Drug resistance found to vary by ethnicity

Steven l Teitelbaum MD

Aenetic mutation affecting resistance to chemotherapy occurs more freshyquently in some ethnic groups than

in others according to a new study Researchers found that African and

African-American populations included more individuals with the drug-resistant gene than Caucasian or Asian populashytions This might help explain why some people of African descent respond poorly to chemotherapy The research was presented March 25 2000 at the annual meeting of the American Association for Cancer Research in New Orleans

We now know that the genetic influence on drug resistance is not the same throughout the whole populashytion says Howard L McLeod PharmO associate professor of medicine of pharshymacology and molecular biology and of genetics Because of this work we can try to solve the problem

McLeod who led the international team of researchers from his previous position at the University of Aberdeen in the United Kingdom specializes in pharshymacogenetics an emerging research field

Margaret-Mary Ameyaw MO PhD of the University of Aberdeen is the studys first author and will join the Washington University faculty later this year

The mutation studied by McLeod and his colleagues changes production of a protein called P-glycoprotein or PGP a molecular pump that rids cells of drugs When working correctly PGP pumps chemotherapeutic drugs out of tumors allowing the tumor cells to survive This

response is known as drug resistance The genetic mutation means the PGP pump stops working allowing drugs to enter and kill tumor cells

Working with collaborators in five countries McLeod and his colleagues did DNA tests on blood samples from 1280

people from 10 ethnic populations They found that some populations were sigshy

nificantly more likely than others to contain the mutation The groups of African descent-Ghanaian Kenyan African American and Sudaneseshyhad the mutation significantly less

frequently than Caucasian and Asian populations tested

Because lack of the mutation is associated with higher expression

of PGP and thus higher drug resistance these findings mean that physicians may soon have the necessary tools for individushyalizing therapy especially for people of African heritage Extreme interventions such as gene therapy would not be necessary because an existing medication that chemically inhibits the PGP protein could be given to people found to overexpress PG P

4 Pulse Summer 200 I Outlook

Students faculty receive Academic Womens Network 2001 awards THREE STUDENTS AND TWO PROFESSORS

recently were recognized for their achievements by the

universitys Academic Womens Network (AWN)

Each year the AWN recognizes graduating students

in either the MD or PhD programs at the medical

school based upon their demonstrated outstanding leadshy

ership in service ro or advancement of women within the

community This years Student Leadership Awards went

to Leah Bernstein PhD Emily Cronbach MD and

Alison Stuebe MD

Bernstein published two I1rst-author publications

and contributed ro a third during her graduate work in

neuroscience Her thesis project focused on the localizashy

tion and regulation of the so-called RGS proteins or

Regularors of G protein Signaling Additionally she has

been active in neuroscience education and in student

government

Cronbach is a summa cum laude graduate of

San Francisco State with a bachelors degree in 111m

Prior ro entering medical school she worked on several

documentaries related to teenagers and HIV She was the

co-organizer of the Reproductive Options Education

program a forum for debate on ethical issues in reproshy

ductive health and she served as co-coordinator of the

student chapter of the American Medical Womens

Association (AMWA) through which she developed a

fourth-year elective in outpatient womens health She

was selected for Alpha Omega Alpha the national

medical honor society

Stuebe is a summa cum laude graduate of Duke

University who came to Washington Universiry after

a st int as producer for the New York Times online site

on womens health She was awarded the School of

Medicines Mr and Mrs Spencer T Olin Fellowship for

Women and also was selected for Alpha Omega Alpha

Stuebe was instrumental in creating the School of

Medicines career counseling web site which she preshy

sented at the 1999 American Association of Medical

Colleges (AAMC) national meeting She was active as

co-coordinator of the student chapter of AMWA and

served on the groups national web site task force

The AWN presented its 2001 Mentor Awards to

twO faculty members Linda B Cotder PhD and

Herberr W Virgin IV MD PhD

Cotder professor of psychiatry (epidemiology)

joined the Washington University faculty in 1990 She

received her MPH from Boston University School of

Public Health in 1980 and her PhD from Washington

University in 1987 Virgin is an associate professor in medicine in

molecular microbiology and in pathology and immunolshy

ogy He received his MDPhD from Harvard University

and joined the Washington University faculty in 1991

Outstanding Student Researcher Third-year medical student Clint Walker (center) receives the Alpha Omega Alpha (AOA) 2001 Student Research Fellowship Award from Scot G Hickman M0 (left) professor of medicine and president of the School of Medicines AOA chapter Walker was awarded $3000 in support of his research on peripheral nerves His advisers on the project are fellow John Winograd MD (right) and Susan E Mackinnon MD professor and head of the division of plastic and reconstructive surgery

Outlook Su m mer 2001 Pulse 5

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

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~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

Gelberman named AAOS president RICHARD H GELBERMAN MD the Fred C Reynolds

Professor and head of orthopaedic surgery recently became

presidenc of the 25500-member American Academy of

Orchopaedic SurgelY (AAOS) at its 68th annual meeting

and scientific sess ions in San Francisco CA

A mem ber of the academy since 1981 Gelberman

h as served on more than a dozen of its committees and

task fo rces Most recently he had been one of the organishyza tions vice presidents As president he plans to initiate

a new program designed to improve musculoskeletal care

for the public through better education for doctors

Gelberman also is chief of hand and wrist surgery

and director of the hand and upper extremity fellowship

traini ng program at the School of Medicine and is

orthopaedic-surgeon-in-chief at Barnes-Jewish and

St Louis Childrens hospitals

H e has had support from

the N ational Institutes of

H ealth for his research on

dense regular connective tisshy

sue since 1976 He also has

research interests in radius

fractures ca rpal instabili ty

and nerve injuries

Gelberman is the author

Richard H Gelberman MD of more than 200 scientific man uscripts and has received

many awards for his research He has served on the editoshy

rial boards of several medical publications and currently

serves as a reviewer for the Journal of Bone and Joint Surger)1 and the Journal ofOrthopaedic Research

The AAOS is a no t-for-profit organization that

provides education programs for orthopaedic surgeons

allied health professionals and the public

NEUROLOGY

Mild cognitive impairment appears to be AlzheimerS disease OST PEOPLE DIAGNOSED with mild

cognitive impairment (Mel) evenrualJy

develop Alzheimers disease researchers with

the School of Medicines Memory and Aging

Project (MAP) have found The results suggest that Mel

characterized by minor memory loss is an early stage of

Alzheimers rather than a separate disorder

that the subtle signs of memory loss might indicate the

onset of Alzheimers disease

The volunteers were reassessed annually for up to

95 years After five years Alzheimer symptoms had

developed in 68 percent of the healthy volunteers

199 percent of the individuals in the uncertain MCl

group 357 percent of those in the suspicious group and

We were surprised to find that an 605 percent of those in the fairly

unexplained memory deficit that is curshy confident group By 95 years all of

rendy called MCl almost always turns the volunteers with the most severe

out to be early Alzheimers says John form ofrvlCl had developed the

C Morris MD Harvey A and clinical symptoms of Alzheimers

Dorismae H acker Friedman Professor Forry-two participants died before

of Neurology director of MAP and the end of the srudy and donated

co-director of the Alzheimers Disease their brains for postmortem analysis

Research Center He is first author of a the only way to diagnose Alzheimers

paper on the subject that appeared in disease with complete accuracy

the March issue ofArchives ofNeurology Autopsies of 25 volunteers who origishy

nally were diagnosed with MCIResearchers examined 404 people

who had either mild memory loss or no memory probshy

lems and who volunteered for annual memory assessshy

ments at MAP between July 1990 and June 1997 The

227 individuals with MCI were placed into one of three

categories fairly confident suspicious and uncertain The

categories reAected the researchers degree of confidence

Outlook Summer 2001

confirmed that 21 had Alzheimers disease

Morris points out that these results are based on a

select group of individuals who volunteered for memory

research Even with that caveat the findings are impresshy

sive he says Earlier diagnosis will help scientists develop

more etTective therapies for early intervention

Pulse 3

The mission of FASEBTeitelbaum is FASER president-elect is ro en hance che abili ry of

STEVEN L TEITELBAUM MD has been selected as biomedical and life sciemiscs

the nexc presidenr-elect of the Federation of American ro improve through cheir

Sociecies for Experimencal Biology (FASEB) effeccive research the healch wellshy

July 1 2001 FASEB is che largest coaJicion of biomedical being and productivity of

research associations in che United States represeming all people The organization

21 sociecies wich more chan 60000 members serves the imerests of these

Teicelbaum who is che Wilma and Roswell Messing sciemists particularly in

Professor of Pathology will serve as che groups president areas related to publ ic policy

in 2002-2003 Also a pathologist ac Barnes-Jewish The group also facilitaces coalicion activi ties among

Hospital and Sc Louis Shriners HospitaJ Teitelbaum member societies and di sseminaces information on

sets a primary goal in his new role to promoce federal biological research through scientific conferences and

funding of biomedical and life sciences research publications

PHARMACOGENETICS

Drug resistance found to vary by ethnicity

Steven l Teitelbaum MD

Aenetic mutation affecting resistance to chemotherapy occurs more freshyquently in some ethnic groups than

in others according to a new study Researchers found that African and

African-American populations included more individuals with the drug-resistant gene than Caucasian or Asian populashytions This might help explain why some people of African descent respond poorly to chemotherapy The research was presented March 25 2000 at the annual meeting of the American Association for Cancer Research in New Orleans

We now know that the genetic influence on drug resistance is not the same throughout the whole populashytion says Howard L McLeod PharmO associate professor of medicine of pharshymacology and molecular biology and of genetics Because of this work we can try to solve the problem

McLeod who led the international team of researchers from his previous position at the University of Aberdeen in the United Kingdom specializes in pharshymacogenetics an emerging research field

Margaret-Mary Ameyaw MO PhD of the University of Aberdeen is the studys first author and will join the Washington University faculty later this year

The mutation studied by McLeod and his colleagues changes production of a protein called P-glycoprotein or PGP a molecular pump that rids cells of drugs When working correctly PGP pumps chemotherapeutic drugs out of tumors allowing the tumor cells to survive This

response is known as drug resistance The genetic mutation means the PGP pump stops working allowing drugs to enter and kill tumor cells

Working with collaborators in five countries McLeod and his colleagues did DNA tests on blood samples from 1280

people from 10 ethnic populations They found that some populations were sigshy

nificantly more likely than others to contain the mutation The groups of African descent-Ghanaian Kenyan African American and Sudaneseshyhad the mutation significantly less

frequently than Caucasian and Asian populations tested

Because lack of the mutation is associated with higher expression

of PGP and thus higher drug resistance these findings mean that physicians may soon have the necessary tools for individushyalizing therapy especially for people of African heritage Extreme interventions such as gene therapy would not be necessary because an existing medication that chemically inhibits the PGP protein could be given to people found to overexpress PG P

4 Pulse Summer 200 I Outlook

Students faculty receive Academic Womens Network 2001 awards THREE STUDENTS AND TWO PROFESSORS

recently were recognized for their achievements by the

universitys Academic Womens Network (AWN)

Each year the AWN recognizes graduating students

in either the MD or PhD programs at the medical

school based upon their demonstrated outstanding leadshy

ership in service ro or advancement of women within the

community This years Student Leadership Awards went

to Leah Bernstein PhD Emily Cronbach MD and

Alison Stuebe MD

Bernstein published two I1rst-author publications

and contributed ro a third during her graduate work in

neuroscience Her thesis project focused on the localizashy

tion and regulation of the so-called RGS proteins or

Regularors of G protein Signaling Additionally she has

been active in neuroscience education and in student

government

Cronbach is a summa cum laude graduate of

San Francisco State with a bachelors degree in 111m

Prior ro entering medical school she worked on several

documentaries related to teenagers and HIV She was the

co-organizer of the Reproductive Options Education

program a forum for debate on ethical issues in reproshy

ductive health and she served as co-coordinator of the

student chapter of the American Medical Womens

Association (AMWA) through which she developed a

fourth-year elective in outpatient womens health She

was selected for Alpha Omega Alpha the national

medical honor society

Stuebe is a summa cum laude graduate of Duke

University who came to Washington Universiry after

a st int as producer for the New York Times online site

on womens health She was awarded the School of

Medicines Mr and Mrs Spencer T Olin Fellowship for

Women and also was selected for Alpha Omega Alpha

Stuebe was instrumental in creating the School of

Medicines career counseling web site which she preshy

sented at the 1999 American Association of Medical

Colleges (AAMC) national meeting She was active as

co-coordinator of the student chapter of AMWA and

served on the groups national web site task force

The AWN presented its 2001 Mentor Awards to

twO faculty members Linda B Cotder PhD and

Herberr W Virgin IV MD PhD

Cotder professor of psychiatry (epidemiology)

joined the Washington University faculty in 1990 She

received her MPH from Boston University School of

Public Health in 1980 and her PhD from Washington

University in 1987 Virgin is an associate professor in medicine in

molecular microbiology and in pathology and immunolshy

ogy He received his MDPhD from Harvard University

and joined the Washington University faculty in 1991

Outstanding Student Researcher Third-year medical student Clint Walker (center) receives the Alpha Omega Alpha (AOA) 2001 Student Research Fellowship Award from Scot G Hickman M0 (left) professor of medicine and president of the School of Medicines AOA chapter Walker was awarded $3000 in support of his research on peripheral nerves His advisers on the project are fellow John Winograd MD (right) and Susan E Mackinnon MD professor and head of the division of plastic and reconstructive surgery

Outlook Su m mer 2001 Pulse 5

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

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~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

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Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

The mission of FASEBTeitelbaum is FASER president-elect is ro en hance che abili ry of

STEVEN L TEITELBAUM MD has been selected as biomedical and life sciemiscs

the nexc presidenr-elect of the Federation of American ro improve through cheir

Sociecies for Experimencal Biology (FASEB) effeccive research the healch wellshy

July 1 2001 FASEB is che largest coaJicion of biomedical being and productivity of

research associations in che United States represeming all people The organization

21 sociecies wich more chan 60000 members serves the imerests of these

Teicelbaum who is che Wilma and Roswell Messing sciemists particularly in

Professor of Pathology will serve as che groups president areas related to publ ic policy

in 2002-2003 Also a pathologist ac Barnes-Jewish The group also facilitaces coalicion activi ties among

Hospital and Sc Louis Shriners HospitaJ Teitelbaum member societies and di sseminaces information on

sets a primary goal in his new role to promoce federal biological research through scientific conferences and

funding of biomedical and life sciences research publications

PHARMACOGENETICS

Drug resistance found to vary by ethnicity

Steven l Teitelbaum MD

Aenetic mutation affecting resistance to chemotherapy occurs more freshyquently in some ethnic groups than

in others according to a new study Researchers found that African and

African-American populations included more individuals with the drug-resistant gene than Caucasian or Asian populashytions This might help explain why some people of African descent respond poorly to chemotherapy The research was presented March 25 2000 at the annual meeting of the American Association for Cancer Research in New Orleans

We now know that the genetic influence on drug resistance is not the same throughout the whole populashytion says Howard L McLeod PharmO associate professor of medicine of pharshymacology and molecular biology and of genetics Because of this work we can try to solve the problem

McLeod who led the international team of researchers from his previous position at the University of Aberdeen in the United Kingdom specializes in pharshymacogenetics an emerging research field

Margaret-Mary Ameyaw MO PhD of the University of Aberdeen is the studys first author and will join the Washington University faculty later this year

The mutation studied by McLeod and his colleagues changes production of a protein called P-glycoprotein or PGP a molecular pump that rids cells of drugs When working correctly PGP pumps chemotherapeutic drugs out of tumors allowing the tumor cells to survive This

response is known as drug resistance The genetic mutation means the PGP pump stops working allowing drugs to enter and kill tumor cells

Working with collaborators in five countries McLeod and his colleagues did DNA tests on blood samples from 1280

people from 10 ethnic populations They found that some populations were sigshy

nificantly more likely than others to contain the mutation The groups of African descent-Ghanaian Kenyan African American and Sudaneseshyhad the mutation significantly less

frequently than Caucasian and Asian populations tested

Because lack of the mutation is associated with higher expression

of PGP and thus higher drug resistance these findings mean that physicians may soon have the necessary tools for individushyalizing therapy especially for people of African heritage Extreme interventions such as gene therapy would not be necessary because an existing medication that chemically inhibits the PGP protein could be given to people found to overexpress PG P

4 Pulse Summer 200 I Outlook

Students faculty receive Academic Womens Network 2001 awards THREE STUDENTS AND TWO PROFESSORS

recently were recognized for their achievements by the

universitys Academic Womens Network (AWN)

Each year the AWN recognizes graduating students

in either the MD or PhD programs at the medical

school based upon their demonstrated outstanding leadshy

ership in service ro or advancement of women within the

community This years Student Leadership Awards went

to Leah Bernstein PhD Emily Cronbach MD and

Alison Stuebe MD

Bernstein published two I1rst-author publications

and contributed ro a third during her graduate work in

neuroscience Her thesis project focused on the localizashy

tion and regulation of the so-called RGS proteins or

Regularors of G protein Signaling Additionally she has

been active in neuroscience education and in student

government

Cronbach is a summa cum laude graduate of

San Francisco State with a bachelors degree in 111m

Prior ro entering medical school she worked on several

documentaries related to teenagers and HIV She was the

co-organizer of the Reproductive Options Education

program a forum for debate on ethical issues in reproshy

ductive health and she served as co-coordinator of the

student chapter of the American Medical Womens

Association (AMWA) through which she developed a

fourth-year elective in outpatient womens health She

was selected for Alpha Omega Alpha the national

medical honor society

Stuebe is a summa cum laude graduate of Duke

University who came to Washington Universiry after

a st int as producer for the New York Times online site

on womens health She was awarded the School of

Medicines Mr and Mrs Spencer T Olin Fellowship for

Women and also was selected for Alpha Omega Alpha

Stuebe was instrumental in creating the School of

Medicines career counseling web site which she preshy

sented at the 1999 American Association of Medical

Colleges (AAMC) national meeting She was active as

co-coordinator of the student chapter of AMWA and

served on the groups national web site task force

The AWN presented its 2001 Mentor Awards to

twO faculty members Linda B Cotder PhD and

Herberr W Virgin IV MD PhD

Cotder professor of psychiatry (epidemiology)

joined the Washington University faculty in 1990 She

received her MPH from Boston University School of

Public Health in 1980 and her PhD from Washington

University in 1987 Virgin is an associate professor in medicine in

molecular microbiology and in pathology and immunolshy

ogy He received his MDPhD from Harvard University

and joined the Washington University faculty in 1991

Outstanding Student Researcher Third-year medical student Clint Walker (center) receives the Alpha Omega Alpha (AOA) 2001 Student Research Fellowship Award from Scot G Hickman M0 (left) professor of medicine and president of the School of Medicines AOA chapter Walker was awarded $3000 in support of his research on peripheral nerves His advisers on the project are fellow John Winograd MD (right) and Susan E Mackinnon MD professor and head of the division of plastic and reconstructive surgery

Outlook Su m mer 2001 Pulse 5

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

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~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

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Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

Students faculty receive Academic Womens Network 2001 awards THREE STUDENTS AND TWO PROFESSORS

recently were recognized for their achievements by the

universitys Academic Womens Network (AWN)

Each year the AWN recognizes graduating students

in either the MD or PhD programs at the medical

school based upon their demonstrated outstanding leadshy

ership in service ro or advancement of women within the

community This years Student Leadership Awards went

to Leah Bernstein PhD Emily Cronbach MD and

Alison Stuebe MD

Bernstein published two I1rst-author publications

and contributed ro a third during her graduate work in

neuroscience Her thesis project focused on the localizashy

tion and regulation of the so-called RGS proteins or

Regularors of G protein Signaling Additionally she has

been active in neuroscience education and in student

government

Cronbach is a summa cum laude graduate of

San Francisco State with a bachelors degree in 111m

Prior ro entering medical school she worked on several

documentaries related to teenagers and HIV She was the

co-organizer of the Reproductive Options Education

program a forum for debate on ethical issues in reproshy

ductive health and she served as co-coordinator of the

student chapter of the American Medical Womens

Association (AMWA) through which she developed a

fourth-year elective in outpatient womens health She

was selected for Alpha Omega Alpha the national

medical honor society

Stuebe is a summa cum laude graduate of Duke

University who came to Washington Universiry after

a st int as producer for the New York Times online site

on womens health She was awarded the School of

Medicines Mr and Mrs Spencer T Olin Fellowship for

Women and also was selected for Alpha Omega Alpha

Stuebe was instrumental in creating the School of

Medicines career counseling web site which she preshy

sented at the 1999 American Association of Medical

Colleges (AAMC) national meeting She was active as

co-coordinator of the student chapter of AMWA and

served on the groups national web site task force

The AWN presented its 2001 Mentor Awards to

twO faculty members Linda B Cotder PhD and

Herberr W Virgin IV MD PhD

Cotder professor of psychiatry (epidemiology)

joined the Washington University faculty in 1990 She

received her MPH from Boston University School of

Public Health in 1980 and her PhD from Washington

University in 1987 Virgin is an associate professor in medicine in

molecular microbiology and in pathology and immunolshy

ogy He received his MDPhD from Harvard University

and joined the Washington University faculty in 1991

Outstanding Student Researcher Third-year medical student Clint Walker (center) receives the Alpha Omega Alpha (AOA) 2001 Student Research Fellowship Award from Scot G Hickman M0 (left) professor of medicine and president of the School of Medicines AOA chapter Walker was awarded $3000 in support of his research on peripheral nerves His advisers on the project are fellow John Winograd MD (right) and Susan E Mackinnon MD professor and head of the division of plastic and reconstructive surgery

Outlook Su m mer 2001 Pulse 5

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

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8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

~ul e International cooperation William A Peck MD executive vice chancellor for medical affairs and dean of the School of Medicine welcomes Clifford Nii Boi Tagoe MB ChB PhD dean of the University of Ghana Medical School during a recent visit The two medical schools along with BJC International Healthcare Services and the Missouri Department of Economic Development discussed potential collaboration regarding HIV programs in Ghana Africa Graphic The HIV virion

Neufeld recipient of Rudin glaucoma prize for work in protecting nerve cells ARTHUR H NEUFELD PHD the Bernard Becker

Research Professor of Ophthalmology and Visual

Sciences at the School of Medicine has been awarded

the 2000 Lewis Rudin Prize by the New York Academy

of Medicine The Rudin Prize is given annua ll y for

outstanding glaucoma research published during the

prevlOus year

Neufeld showed that protecring reti nal nerve cells can

help p revem damage in a chronic model of glaucoma

In a 1999 paper in the Proceedings ofthe NationaL Academy ofSciences Neufeld and colleagues reported on

experiments involving an animal model of glaucoma

Xorking in rats with elevated eye pressure they were

able ro prevenr loss of retinal ganglion cells by inhibiting

the action of an enzyme that makes nitric oxide

With co-authors Akira Sawada MD and Bernard

Becker MD N eufeld demonstrated that an agem ca lled

aminoguanidine significanrly limited retinal ganglion cell

loss Aminoguanidine inhibits the acriviry of the enzyme

that makes nitric oxide called inducible nitric oxide

synthase (NOS-2)

G laucoma a disease in which patienrs first lose

peripheral and then central vision affects more than

3 million adu lts and is the second-leading leading cause

of irreversib le vision loss in the United States More than

G Pulse

80000 Am ericans with glaucom a are legally blind from

the disease and it is the No1 cause of blindness in

African Americans

Neufeld has received many grants from the N ational

Institutes of Health to suPPOrt hi s research Currenrly

he is principal investigaror on the granr Pharmacoshy

logical Neuroprotection in

Glaucoma which has been

helping ro suppOrt his

research aimed at inhibiting

NOS-2 in the eye

Over the last two

decades Neufeld has served

the Eye Research Institute

of Retina Foundation in a

variery of capaci ties including

direcror of research He also

is a member of the Glaucoma Foundations Scientific

Advisory Board He sits on the editoria l board of the

JournaL ofOcuLar PharmacoLogy and Therapeutics and he

is a longtime member of the Association for Research

in Vision and Ophthalmology serving both as a trustee

and as that groups president in 1984

The Rudin Prize was established in 1995 and is

funded by the Samuel and May Rudin Foundation

Summer 2001 Outlook

Arthur H Neufeld Phil

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

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8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

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igt~- LIP I 1 bull bull rmiddot bull

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Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

bull

Rose A Walker

New Center for Advanced Medicine names Walker Tucker co-directors ROSE A WALKER AND KIMBERLY TUCKER

will team up to direct the Center for Advanced Medicine

(CAM) the new ambulatory care center scheduled

to open in November 2001

Walker will represent the

School of Medicine and

Tucker will represent

Barnes-Jewish Hospital

In her new position

WaJker will coordinate clinical

operations and policies with

the 14 clinical centers housed

in the Center for Advanced

Medicine She will work with

Tucker on issues that cross institutional and departmental

management lines such as service issues affecting patients

As a liaison she will assist patients or faculty members

with concerns that arise among departments or between

the medical school and the hospital

Walker who played a critical role in developing

the Center for Advanced Medicine also is director of

ambulatory operations

for the Facul ty Practice

Plan She formerly worked

as a nurse clinician and a

nursing administrator for

inpatient and ambulatory

services at Barnes-Jewish

Hospital and as a physician

practice administrator for

the medical school Kimberly Tucker

Tucker will coordinate

the centers operational responsibilities related to Barnesshy

Jewish Hospital She will establish standards of practice

and care and develop policies and procedures in collaboshy

ration with Walker

A clinical manager Tucker has been in management

at Barnes-Jewish Hospital since 1987 She earned a

bachelors degree in nursing from the University of

Missouri-St Louis and she is completing a masters

degree in nursing from the Jewish Hospital College of

Nursing and Allied Health Additionally Tucker has

served in leadership roles for the American Association

of Critical Care Nurses and is a member of the American

College of Health Care Executives

Outlook Summer 2001

Andrew C Heath PhD professor of psychiatry left and Kathleen K Bucholz PhD research associateprofessor of psychiatry talk with psychiatry department chair and Samuel B Guze Professor Charles F Zorumski M0 at the inaugural symposiumnamed in Guzes honor

First Guze Symposium held E MISSOURI ALCOHOLISM RESEARCH

CENTER (MARC) recently hosted the first

Guze Symposium to discuss the latest in clinical

practice research and treatment for alcoholism

The Guze Symposium was named in honor of

the late Samuel B Guze MD a pioneer of the medical

model of psychiatric illness and in the field of alcoshy

holism research His early studies of alcohol use and

abuse were important in the movement to consider

alcoholism a disease rather than a character flaw

U e joined the faculey in 1951 and later served

as vice chanccllor fo r medical affairs and president of

the Washington University Medical Center from 1971

to 1989 He also served as head of psychiatry from

1971 to 1989 and again from 1993 to 1997

The symposium featured local and national

experts on topics such as genetic studies of alcoholism

the role of depression and anxiety di~o rders in alcoshy

holism treatment for alcoholism and drug abuse and

the consequences of alcohol abuse by adolescents

Created by a $67 million grant from the

National Institute on Alcohol Abuse and Alcoholism

(NlAAA) at the National Institutes of Health the

MARC is one of 15 NIH-funded alcoholism research

centers

Housed at Washington University the center

also involves investigators from Saint Louis University

University of Missouri-Columbia St Louis and

Palo Alto CA Veterans Administrations and the

Queensland Institute for Medical Research in

Brisbane Australia

Pulse 7

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

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~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

c eclearyn

An age-related disease that compromises your most critical vision responds to a promising new therapy by Candace OConnor

OR AN OLDER ADULT LIKE DOROTHY BEIMFOHR

who loves to read and needs to drive age-related

macular degeneration (AMD) is a terrifYing diagnosis

When I first heard that it really just shook me she says

How would this eye disease-in which abnormal blood

vessels creep under the center of the retina leaking blood

and destroying vision-change her life Would it curtail

her pleasant visits to the Mascoutah Illinois library

Would it rob her of the sight of her five grandchildren

When patients lose their center

of vision you cant tell by looking at

them that they are handicap ped

says Nancy M Holekamp MD

Above Dorothy Beimfohr AMD patient assistant professor of clinical ophshy

thalmology who treated Beimfohr

Facing page Do you take your percepshy But they wont recognize you

tion of a simple grid for granted because they cant see your face they

Patients with macular degeneration have a hard time dialing your phone

may lose the ability to clearly see number and if you ask them to read

these lines-and the things they love something they cant Consequently

in life -even overnight they lose a lot of their independence

8 I Can See Clearly Now

This disease the leading cause of

blindness in people 65 and older is

nOt only devastating for patients-

it also is frustrating for their physishy

cians AMD sufferers who otherwise

may be in perfect health become so

desperate that they sometimes resort

to sham treatments in an attempt to

find a cure And ophthalmologists

armed with few clinical weapons to

fight the disease have litde they can

do to help

At the Barnes Retina Institute

(BRI) a national leader in retinal

research Washington University facshy

ulty members are involved in several

clinical trials that are testing new

therapies aimed at saving or restorshy

ing vision in AMD patients In fact

BRI faculty members have particishy

pated in most of the major trials that

have taken place over th e past several

decades A recent trial that examined

a new approach (0 treating AMD

photodynamic therapy has shown

promising results

Summer 2001 Outlook

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

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8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

W nte center of sigh fails The center of the retina called the macula is highly detail-sensitive allowing you to read this page or recognize your friends face Macular degeneration attacks this critical area of vision

AM 0 comes in two basic forms The dry type is characterized by spots called driisen and sometimes by atrophy of the tissue layer that underlies the retina No treatment exists for dry AMD but H is also a milder more slowly progressive disease that only accounts for 10 percent of severe vision loss among AMD patients

Wet AMD The story is much different with the second wet form of the disease in which blood and fluid from abnormal blood vessels leak onto sensitive photoreceptors in the macula Among AM 0 patients this type of the disshyease accounts for 90 percent of all severe vision loss Often this change occurs sudshydenly without warning

It is not yet known exactly why this happens Attempts to link AM 0 to smoking or diet have not been successful It is rare in Asian and African-American patients and most common in women 60 and older of Scandinavian descent There may be a hereditary component to the disease -but what stands out is its correlation with age The longer you live the more likely you are to develop it

Healthy retina

Appearance of age spots call ed driisen

Macula with wet macular degeneration (abnormal blood vessels) impedes central detail vision

Searching for effective treatment We see thousands of pa tients a yea r

with macular degeneration they make

up at leas t 25 percent of our caseshy

load says M Gilbert G rand MD

professor of cl inical ophthalmology

Th is is a very signi ficant problem

and we are continuing ro see more

of it as the popu lation ages Among

the saddes t aspects has been having

ro tell patien ts that we have limited

forms of trea tment

In the late 1980s and early

1990s Washingron University and

o ther institutions particip ated in

the Macular Phorocoagulation Study

sponsored by the Na tionallnsti(Utes

of Health which targeted patients

wi th wet AMD The firs t p hase of this

trial foc used on pati ents whose blood

vesse ls had pene trated the macula

but had not yet reached the fovea

its tiny 500-micron-wide cenrer

In the study gro up clinic ians

used a conventional thermal laser

ro destroy the vessels in the con tro l

group pa tients did not receive laser

trea tment T he res ults showed that

lase r therapy was effective but it

was not a perfect solution Nearly

50 percent of the ti me the vessels

grew back-and the laser was

dest ruc tive creat ing a blind spOt

where it did its work

St ill the results were posit ive

enough that researchers went fu rth er

studying pa tients whose blood vesshy

sels had grown inro the fovea T he

laser treatment again yielded m ixed

resu lts It destroyed the blood vessels

and stymied their regrowth but it

also destroyed the cente r of vision

rendering pat ients legally blind Even

so 18 months after trea tment the

trea ted pa ti ents were better off than

the untreated control group

Summer 200 1 Ou tl ook

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

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~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

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igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

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Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

Nancy M Holekamp MO examines the eye of patient Sametta House

About the same time two

Washington University ophthalmolshy

ogists-Matthew A Thomas MD

of the BRI and former department

head Henry] Kaplan MDshy

pioneered an extraordinary form of

surgery in which they elevated or

focally detached the retina plucked

out the errant blood vessels and then

put the retina back in place A mulshy

ticenter clinical trial cu rren rly in

progress with Thomas as national vice

chairman is evaluating the success of

this surgery but it appears so far that

it works best in younger patients

Other trials are ongoing A

national NIH-sponsored study-the

Complications of AMD Prevention

Trial (CAPT)-with Grand as prinshy

cipal investigator is studying the

use of low-power laser to treat dry

AMD which can be a precursor to

the wet form of the disease

BRI physicians also are

participating in a study of macular

translocation surgery developed

at Johns Hopkins And they are

enrolling patients in a trial sponshy

sored by Alcon Research Ltd to

see whether a new compound

anecortave acetate StopS the leakage

from these abnormal blood vessels

Outlook Summer 2001

Photodynamic therapy may be one answer But the latest and most promising

form of AMD treatment is the

photodynamic therapy (PDT) that

Dorothy Beimfohr underwent in

which a non-thermal laser targets

leaky blood vessels

Washington University particishy

pated in the clinical trials of PDT

which was approved by the FDA in

April 2000 for one form of AMD

Already BRI physicians use it daily

and that usage may soon increase

since the FDA is on the verge of

approving its use in other forms of

AMD In addition PDT has strong

potential for treating patients with

other retinal diseases

Beimfohr is delighted with the

Outcome of her PDT treatment

While many patients have bilateral

disease her left eye has not been

affected Bu t the vision in her disshy

eased right eye has improved from

20-80 to 20-40- enabling her to

drive once again

PDT is an ingenious idea says

Holekamp The eye is set up pershy

fecdy for this type of novel therapy

And it only destroys the abnormal

blood vessels without hurting the

retina which is a huge advantage

The treatment is easy quick

and painless The trick is to catch

patients when they are just beginshy

ning to lose vision since those who

have had the disease for years -

and have formed retinal scar tissue

-will not benefit from any cUlTenrly

available treatment

Retina specialists initial1y pershy

form a fluorescein angiogram test to

determine which patients are eligible

for PDT treatment

When Beimfohr came in for

her PDT treatment she received a

I O-minute infusion of photoporshy

phyrin dye Visudynetrade into a vein

in her arm The dye coursed through

all the blood vessels in her body

including the abnormal vessels in

her retina Then Holekamp shone

the non-destructive laser at her eye

for 83 seconds Throughout the

procedure Beimfohr was fully

awake afterwards she only had to

avoid direct sunlight for five days

Following treatment ophthalshy

mologists re test PDT-trea ted patients

at three-month intervals to detershy

mine whether any regrowth has

occurred If it has they repeat the

treatment

Beimfohr was fortunate - not

only did the photodynamic therapy

prevent the abnormal blood vessels

from returning her vision actually

improved

In the clinical trial of PDT

67 percent of patients who received

the treatment were stabilized or

improved by it Only 16 percent

however had a return of good vision

So it is not the cure that we

were hoping for says Holekamp

but it is something else that we

have to offer patients who otherwise

have no hope 0

I Can See Clearly Now 1 I

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

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~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

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Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

conun ru m

Heidi Beddingfield infected with HIV for more than 10 years discusses her health with William G Powderly MO clinical

director of the AIOS Clinical Trials Unit (ACTU) at the School of Medicine

HEN FIRST DIAGNOSED WITH HIV IN 1990

Heidi Beddingfield was a carefree I8-year-old still

feeling the invincibility of youth I expected I only had

three years to live but it didnt bother me she says

After all what could I do about it

She was right-there wasnt much that could be done at the

time The few available drugs could only be expected to control the

virus for about a year Besides-it was too much of a hassle for

the teenager to deal with grinding up multiple pills every day and

sticking to a strict regimen

In a way she was lucky Beddingfields virus didnt

Rare up until December 1995 Overnight she went

from feeling invincible to becoming incapacitated

by a bacterial infection that attacked her brain a not

uncommon consequence of an immune system weakshy

ened by HIV Fortunately by that time scientists

had just discovered a new way to treat the disease

by combining three classes of medication

After five weeks on this triple-drug cocktail

Beddingfields viral count decreased drastically after a couple more

weeks her virus qualified as undetectable Six years later her AIDS

is still under control

But theres a catch In 1998 Beddingfield started to dramatically

lose weight Her body is wasting away and doctors now suspect the

very drugs saving her life are to blame

Outlook Summer 2001 The Cocktail Conundrum 13

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

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Go ~ t bull ~ A II~ -~middot ~bull bull - t (14~ r I r ~gt f _~ I

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8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

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igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

J hen the first cocktail component (nucleoside

analogs such as AZT) was introduced in 1987

scientists were optimistic But patients with human

immunodeficiency virus (HIV) the precursor ro

acquired immunodeficiency syndrome (AIDS) sropped

responding ro the medication after just one year of

contlnuous use

In the following yea rs twO new classes of drugs were

quickly approved by the FDA non-nucleoside reverse

transcriptase inhibirors and protease inhibitors By 1995

the FDA recogn ized that combining drugs from these

three classes crippled the virus ability ro replicate The

resulr highly active antiretroviral therapy (HAART)

commonly known as the AIDS drug cock tail

Thanks to the cocktail people with AIDS now are

living considerably longer and healthier lives than before

But the treatment fall s shOrt of physicians initial expecshy

tations The new drugs

may be able to control the bodythe virus but they

cannot eliminate it

Resea rchers have thus tokes far conceded that

patients will have to over remain on medication

for the rest of their lives the course of And as has happened

with the first cocktail the disease component when taken

alone con ti l1UOUS longshyKevll1 E Yorosheski PhD

term use of the cocktail

could result in the develshy

opment of drug-resistant strains of the disease if patients

dont adhere strictly to the drug regimen

The drugs also may not be risk-free as previously

thought As patients like Heidi Beddingfield live longer

with the disease and spend yea rs taking these drugs

new problems arise

Not un til my body started to change did I really

feel all the rhings AIDS robs you of says Beddingfield

you r dignity your self-es teem your appearance and

your physical well-being

Its that las t quality-physical well-being-that her

School of Medicine physicians are focusing on For 14

years the universitys AIDS Clinical Trials Unit (ACTU)

part of the largest consortium of AIDS research centers

in th e world has been ar the forefront of developing new

therapies In 1997 experts here and at other cemers

14 The Cocktail Conundrum

Steven L Teitelbaum MD with fellows Michael Wang MD and Patrick Ross PhD

starred ro notice a dange rous pattern of metabolic

changes such as insulin res istance and high cholesterol

roday these changes are found in roughly half of al l

patients on the cocktail If these effects collectively

termed lipodys trophy cominue to intensify as expected

researchers predict persons taking the cockeail will evenshy

ruall y experience a marked increase in life-threatening

complications such as diabetes heart disease and stroke

Patients with lipodystrophy exhibit at least twO of

the disorders three main symptoms insulin resistance

the precurso r ro diabetes high triglycerides or cholesshy

terol which often leads to hea rt disease and stroke and

a unique pattern of fat distribution Patients with the

disease lose fat from their extremities and their faces

and they gain fat inside the abdomen itself instead of

just below the skin surface and outside the abdominal

wall as in normal weight gain

-he exact cause of lipodystrophy is unclear What1 is known is that HIV makes copies of itself which

then invade other cells The virus recruits each corrupted

cell along the way in a pattern of continuous replication

As patienrs live longer with the cocktails help the virus

has more time ro wreak havoc Also many HIV-positive

patienrs are co-infected with other diseases such as

Hepatitis B As they survive longer these secondary

infections also have more time to affect metabolism

But neirher of these theo ties fully explains the

sudden increased incidence of lipodystrophy noted in

Summer 200 1 Outlook

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

ItI J ~ ~~ bull - ~ --II ~ t

bull rA ~ t~~ 1

- -~bull middot ~~ilir ~~t~11~V~ ~lmiddotmiddot - -~IP middot ~ -

1 fifJ 3 1 r u l 1 ~ J ~- ~_ ~~- - 0 _I ~ - f ~ t1- 4 ~~ r~ c lmiddot ~ middot~Ut~ I t -1I gt - t~ lt middotmiddot middot ~ middot~l I [ ~ il~ ~ Ii ~ 11~ 11 I~ lit ~ ~ ~l Jt ~lt I r ~~a _ Ij~ ~ ~--=- ~l middot ~ bull

~ ~ r~ D ~ ) iii~r~IJbull ~~ u W JII~ JIA- middot~r IoIP 1r I Jlr -1 bull ~

I bull I middot _ - A ~ ~ 1 I l I lt ~~ J r ~ ~~t Ill

Go ~ t bull ~ A II~ -~middot ~bull bull - t (14~ r I r ~gt f _~ I

~ 1 IIIlrJ ~ bull 9

8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

the past few years coincident with introduction of the

third cocktail component protease inhibitors

We believe that the body takes a series of hits

explains Kevin E Yarasheski PhD associate professor

of medicine and that the toxic effects of the anti-HIV

drugs and infection with HIV accumulate over the

course of the disease Scientists propose that protease

inhibitors in and of themselves do not cause lipodystroshy

phy But when taken in conjunction with this sequence

of hits they may trigger undesirable physical and

biochemical changes in the body

Researchers at the ACTU decided to take action

William C Powderly MD co-director of the division of

infectious diseases and professor of medicine assembled

a team led by himself Yarasheski and Samuel Klein MD

the Danforth Professor of Medicine and Nutritional

Science to investigate this emerging problem The team

plans to analyze muscle and fat tissue samples from

lipodystrophy patients and compare them with samples

obtained from HIV-infected individuals who are not

experiencing metabolic changes They also will examine

the contribution of protease inhibitors to these metabolic

changes by carefully altering the components of the

cocktail in certain individuals experiencing side effects

Further insight into the lipodystrophy phenomenon

may provide new hope for patients infected with HIV

and for non-infected individuals with diabetes high

cholesterol or triglycerides or abdominal fat

If we determine the mechanisms underlying the

cause of lipodystrophy in HIV-infected patients we

may be able to develop specific therapies for these comshy

plications or even better help to design drugs that target

the virus but avoid these effects says Powderly The

other spin-off is that this is a model system for very

common disorders such as d iaberes and high cholesterol

in individuals who are not HIV-positive We can use

these new drugs to gain a glimpse of metabolic processes

in normal healthy individuals that we otherwise might

not have found

Washington Universiry researchers already have

made the novel discovery that patients who receive the

drug cocktail are more susceptible to bone softening

such as that which occurs in osteoporosis Steven L Teitelbaum MD the Wilma and Roswell Messing

Professor of Pathology specializes in the basic science

aspect of bone research Already he is using information

from the ACTOs clinical research to study the effects of

HIV on bone cells in mice

Outlook Summer 2001

The Schools clinical AIDS care could soon stretch from St louis to Ethiopia Washington University School returned from a trip to

of Medicine not only has one Meharis home country

of the leading AIDS research Ethiopia where they discussed

programs it also serves the plans for a clinic at the

St Louis community through University of Addis Ababa With

various outreach efforts funds from organizations such One example is the Helena as the World Bank the United

Hatch Special Care Center for Nations and the National

women with HIV which has Institutes of Health the team

become a nationally recognized hopes to establish a center at

center of excellence for comshy the university where they will

prehensive HIV care and clinishy mentor Ethiopian physicians

cal investigations of HIV among and establish a basic AIDS

women therapy program

Soon the School of Were excited about the

Medicines influence may reach possibility of setting up a clinic

as far as Africa where availshy which will be a practical help

ability of the latest medications to people who are in desperate

and information is still scarce need says Clifford Ever the

despite the fact that more than academician I also am eager

25 million people there are to have the opportunity to

now infected with HIV learn more about this infection David B Clifford M0 in a different cultural populashy

and his African research fellow tion Were hopeful that it will

Enawgaw Mehari M0 recently be a very rewarding project

- ~-~ ill I - _--~ ~ II ~ - ~~i~ I I ~IJ - ~shyl 1 4 l ~

ItI J ~ ~~ bull - ~ --II ~ t

bull rA ~ t~~ 1

- -~bull middot ~~ilir ~~t~11~V~ ~lmiddotmiddot - -~IP middot ~ -

1 fifJ 3 1 r u l 1 ~ J ~- ~_ ~~- - 0 _I ~ - f ~ t1- 4 ~~ r~ c lmiddot ~ middot~Ut~ I t -1I gt - t~ lt middotmiddot middot ~ middot~l I [ ~ il~ ~ Ii ~ 11~ 11 I~ lit ~ ~ ~l Jt ~lt I r ~~a _ Ij~ ~ ~--=- ~l middot ~ bull

~ ~ r~ D ~ ) iii~r~IJbull ~~ u W JII~ JIA- middot~r IoIP 1r I Jlr -1 bull ~

I bull I middot _ - A ~ ~ 1 I l I lt ~~ J r ~ ~~t Ill

Go ~ t bull ~ A II~ -~middot ~bull bull - t (14~ r I r ~gt f _~ I

~ 1 IIIlrJ ~ bull 9

8 ~=f~ lii l _~ __~ IJr laquo1__ ami~ ~ L4

~17 - ~ I~_ P-f~ -_ 1 Ethiopian artist Afewerk Tekle created Unity Triptych internationally famous stained-glass windows that confront visitors in the entrance of Africa Hall headquarters of the United Nations Economic Commission for Africa in Addis Ababa Ethiopia if~e piece embodies in three panels Africas sorrowful past present struggles and high aspirations for the future

The Cocktail Conundrum 15

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

Ie uring the first five years of living wi th her disease

Heidi Beddingfield neglected to take her medications

Even with todays improvemenrs in AIDS therapeutics

she ingests a grueling regimen of 30 pills a day Imagine

how much more difficult it would be to keep up with

this rigid schedule for patienrs who also are developing

neurological symptoms such as memory loss or attention

difficulties

Despite treatment advancemenrs some patients are

faced with this added challenge Within days of being

infected with HIV the virus spreads into the central

nervous system (brain and spinal cord) and into periphshy

eral nerves In fact it is puzzling that only some patients

experience the effects of nervous system damage By

understanding these symptoms and determining how

and when they arise researchers hope to improve their

basic understanding of AJDS and to develop new ways

ro treat the infected nervous systems

Just as in lipodystrophy some neurological effects of

HIV may be exacerbated by the roxicity of medications

For example peripheral neuropathy-chronic disabling

pain in peripheral nerves such as those in the feet-actushy

ally worsens with treatment of the virus and is estimated

ro affect at least 30 percent of patients with AIDS In

conrrast the incidence of central nervous system disorshy

ders has decreased since the cocktail was introduced

from roughly 65 percent ro less than 10 percent

The numbers are down but its still a serious probshy

lem says David B Clifford MD the Seay Professor

of Clinical Neuropharmacology in Neurology and vice

David B CliHord MD left confers with research fellow Enawgaw Mehari MD

chairman of neurology Our main concern is what

will happen next because we know this is an area where

the virus is JUSt waiting to spring back and where our

therapies are incomplete

The central nervous system arguably presents the

biggest challenge in understanding how to reach the

virus and halt its destructive effects Medications have a

difficult time getting into the brain because of its natural

protective shield the blood-brain barrier Also scientists

suspect that HIV attacks the brain and spinal cord in

a slightly different fashion than the rest of the body

Clifford therefore is examining the cerebrospinal

fluid-fluid that fills the spaces around the spinal cord

and in the brain-from HIV-positive patients He plans

to measure the activity of the virus in the central nervous

system as cognitive performance changes and hopes

ro determine the effectiveness of HIV medications in

penetrating and helping the nervous system

Another unique challenge is that brain cells are more

sensitive to changes in their environment than other cells

in the body According

If H I V is to Clifford cognitive decline may result from

the sheer presence of

infected immune ceJJs

that release chemicals

not normally found in

the brain environment

ollymole His team currently is

testing a promising drug

Pablo Tcbas MD called selegiline that may

help protect nerve cells

16 The Cocktail Conundrum

Because we cant yet eradicate the

disease there is a low-grade infection in

the brains of all patients with HIV says

Clifford We are concerned that as

patients live longer they may be subject

to an accelerated degenerative disease

similar to Alzheimers

Despite these hurdles one fact

remains These drugs save lives According

ro Pablo Tebas MD medical director

of the ACTU and assistant professor of

medicine HIV is not a death senrence

anymore There is a trade-off in everything

in life and medicine is no exception

But the benefits of understanding the

side effects of therapy will be global 0

Su mmer 2001 Outlook

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

until now

BY GILA

lmmUne systemhe bull

umorsvs bull

y

7 ~)middotI - l ~ ~ 1 8f(

igt~- LIP I 1 bull bull rmiddot bull

bull I bull ~ J

~

Above Robert 0 Schreiber PhD has spent the past eight years exploring whether the Immune system is involved in tumor formation He led the study VijayShankaran M 0 PhD was first author Below The enemy within tissue samples from breast and intestinal tumors ~

Colds and cancer are

different right

But shouldnt the bodys

defensive gatekeepershy

the immune systemshy

guard against both

Research stood in the

face of common senseshy

Z RECKESS

Outlook Summer 2001 The Immune System vs Tumors 17 _______J] I

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

-- ---

CHI CK EN SOUP may soothe

the throat or ca lm an aching

tummy but the immu ne

sys tem ultimately is the bodys rea l

hero scou ring it for danger and

defending it against suspect cells

Bu t what abou t tumor cells Does

the imm une system also protect

aga inst these often dead ly enemies

For years scientis ts expected it

did Bu t studies in the 1970s found

that nude mice - those thought

to lack imm une cel ls called lym phoshy

cytes - d id nOt develop more chemishy

cally induced or spontaneous tumors

than norm al m ice The imm une

sys tem theory was largely abando ned

Bu t so me researchers co ntin ued

to sea rch for a ro le o f the im mu ne

sys tem in tu mor developm ent

determ ined to bridge the gap

beween im m unology and oncology

To that end Robert D Schreiber

PhD the Alumni Professor of

Parhology an d Imm un ology and

p rofessor o f molecul ar microb iology

for med a co llabo rat ion with Lloyd J Old MD director and CEO of

the Ludwi g Institute for Ca ncer

Research at Memorial Sioa nshy

Kettering Cancer C enter in N ew

York Schreiber is known fo r his

research on interferon-gamma (I FNy)

an important protein in the im mune

system while Old is considered

by many to be the grandfather o f

tumor immunology With help

from a team of School of Medicine

researchers the pair h ave determi ned

that the immune system does in

fact appear to protect agains t

rumor form ation

Combined wi th mounting

evidence in the fi eld its a discovery

that could red irect the pu rs uit o f

ca ncer therapies and our undershy

standing o f how the human body

res ponds to infecrion

18 The Immune System vs Tumors

-- - - -~--------- --------shy

Four key findings The immune system eliminates s(

Schreibers team first examined whether mice lacking lymphocytes

developed tumors when exposed to a chemical carcinogen To do so they develshyoped a strain of mice that definitively lacked functional lymphocytes This was accomplished by inactivating a gene found in all lymphocytes RAG2

They then injected the chemical carshycinogen MeA into a group of mice lacking RAG2 and into a group of normal mice Only 19 percent of normal mice developed tumors in contrast with 58 percent of RAG2-deficient mice

In previous studies the group examshyined the effect of MeA on mice lacking either the receptor for IFNy or one of the proteins required for the receptor to function Stat1 Roughly half of these mice also developed tumors

In their current study the researchers also generated mice with two disrupted genes-the gene for RAG2 and the gene

The first two findings show that both I IFNyand lymphocytes interact with

one another to protect individuals from cancer development Thats the good news

But theres also bad news Tumors that developed in normal

mice due to injection of MeA were later transplanted into healthy mice The tumors continued to grow

Tumors from RAG2-deficient mice also were transplanted into healthy mice Eight out of 20 of these were rejected

Apparently the immune systems in healthy carcinogen-free mice were better equipped to recognize-and reject-tumor cells that developed in RAG2-deficient mice (in the absence of a healthy immune system) than tumor cells that had develshyoped in mice with intact lymphocytes

for Stat1 When these doubly-deficient mice were injected with MeA 72 percent of them developed tumors Statistically this was not greater than the incidence of tumors in mice that lacked just one gene or the other Therefore the team concluded that RAG2 and the IFNy receptor have overlapping roles

We think the two are potentially part of the same mechanism but represent different steps in the process explains Schreiber IFNy makes tumor cells expose themselves to the immune system After seeing the abnormal proteins in the tumor the Iympilocytes eliminate the tumor cells

Lymphocytes and IFNy help prevent

formation of chemically induced

tumors

Even a healthy immune system only catches

some tumors-those that escape detection pose

a greater threat As a result of protecting the body

the immune system paradoxically favors the outgrowth of tumors that are less likely to be recognized and killed by the immune system Schreiber says Its a survival of the fittest scenario that works against the host

His immunoediting theory may explain this selective protection If immunoediting is always occurring it can have multiple outcomes he explains If youre lucky the outcome is protection But if youre unlucky transformed tumor cells might alter themselves so the immune system can pick out only a few The others continue growing

Summer 200 1 Outlook

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

tes some tumor cells changes the characteristics of others

Only some human tumors can be directly blamed on chemical carcinoshy

gens Often tumors develop spontaneously without any apparent trigger So Schreiber and colleagues examined whether lymphoshycytes and Stat1 contribute to the natural development of tumors in the absence of a carcinogen

Again they studied three groups of mice-normal RAG2-deficient and those deficient in both RltG-2 and-Stall

After 15 months two of 11 nor mal mice had noncancerous tumors and the rest were tumor-free On the other hand

~ ~11

all 12 RAG2-deficient mice had developed tumors half of which were cancerous Lymphocytes and IFNy help prevent~____-~

f formation of I pontaneous

bull umor

TAP1 can flag tumors making them more t visible to the ~ immune system t

Some tumors that escape immune detection appear to have low levels of

a protein called fAP1 So the scientists added this protein to tumors before transshyplanting them into healthy mice This they hoped would trick the immune system and allow for easier identification of dangerous cells

When highly aggressive tumors such as those that managed to develop in mice with a healthy immune system were transplanted into healthy mice they grew in an extremely rapid manner However when these tumors first were tagged with TAP1 before being transplanted they were rejected

Outlook Summer 2001

Particularly surprising was the fact that mice lacking both RAG2 and Statl seemed to get very sick very quickly All 11 doubly-deficient mice developed tumors well before 15 months Moreover six develshyoped cancerous tumors in the mammary glands This type of cancer rarely occurs in RAG2-deficient mice or in young mice lacking the IFNy receptor

At first glance the higher threat of developing spontaneous tumors in doublyshydeficient mice seems to contradict the first finding that mice lacking both genes are not at a significantly greater risk of develshyoping chemically induced tumors But IFNy also plays a part in non-immune responses According to Schreiber while the roles of lymphocytes and IFNy overlap IFNy also might prevent tumor formation via mechashynisms not involving the immune system

When tagged tumors were transshyplanted into RAG2-deficient mice they still went unnoticed Thus TAP1 facilitated tumor detection and elimination only in the presence of a healthy immune system

We showed that if a tumor is forced to reveal itself to the immune system it often is rejected Schreiber explains We think that a tagged tumor could be used to train the immune system to reject others like it This is very exciting because it indicates that immunotherapy has a significant potential use even for the treatment of tumors that are altered by the immunoediting process

GLOSSARV

lymphocytes White blood cells (immune cells) that detect and kill foreign or diseased cells

RAG2 Gene found in all lymphocytes

IFNy Protein produced by lymphocytes that helps the immune system

The first Haw in the evidence

against the immune system

theory was revealed in the mid-1980s

when two separate studies found

that nude mice were not in fact

completely free of lymphocytes as

previously thought

Schreiber and others later found

signs that both lymphocytes and

IFNy might play important roles in

tumor preventIon

Now in a paper published in

the April 26 2001 issue of the journal

Nature Schreibers team presents the

first conclusive evidence that lymphoshy

cytes and IFNy work together to find

and eliminate tumor cells

When a role for the immune

system in tumor formation was

proposed decades ago scien tists

envisioned a process called immunoshy

surveillance Like a burglar alarm

that detects intruders the immune

system was thought to patrol the

body catching cells at the beginning

of their transformation into suspishy

cious tumor cells

In contrast Schreiber and his

colleagues propose a new model

called immunoediting Like the

security guard editors catch errors

and delete them They also adjust

and tweak areas that need smaller

alterations According to immunoshy

editing the immune system conshy

stantly eliminates certain types of

tumor cells and also changes the

characteristics of others

This sheds light on an ageshy

old controversy and suggests new

possibilities for cancer therapy

says Schreiber 0

Stall Protein required for I FNy to function

TAPl Protein found in low levels in many tumors that escape immune system detection

Doubly-deficient Mice lacking RAG2 and Stat1

The Immune System VS Tumors 19

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

bull bull

Open wide Huebeners cheerful high five helps relieve the office-visit anxieties of children with special health care needs

1)0(10 bull bull OR MANY CHILDREN and indeed

many adults a dentists office is a place

of dread But in the pastel-colored waiting

room of Donald V Huebener DDS MS

at St Louis Childrens Hospital the mood is

upbeat Kids tryout the miniature chairs and Aip

through pop-up books They laugh and chatter

with their parents as if they were in line for a ride

at Six Flags rather than waiting to see the dentist

One teenager takes a nap in his sear

When it is 9-year-old Seans turn he goes in

to greet Huebener with a smile and a handshake

His mother Dee Ann Godlewski follows watchshy

fully Hes always happy to see Dr Don she

says but when the chair leans back he gets

nervous Its only natural after all hes been

through

Sean was born with

a cleft lip and palate and

has had 18 surgeries in his

young life But Huebener

professor of plastic and

reconstructIve surgery

who supervises the four

dental residents and two

assistants in pediatric

dentistry at Childrens

Outlook Summer 2001

U6ing a double d06e o~ medical 6kiLL and candor Donald V Huebener DDS MS provide6 6pecia[-care dentiMry brom cradle to graduation

BY DAVID LINZEE

has had plenty of experience putting children at

ease during his 30 years at Washington University

He takes Sean through his checkup step by step

explaining what he is about to do and rewarding

cooperation with compliments Soon the visit is

over and Sean bounds from the chair with a big

smile Im done he booms Thanks There

remains only a visit to the prize drawer from

which he selects a stretchy alien guy

Not all of Seans visits go this smoothly but

his strong relationship with Huebener has guided

him over the rough spots Dr Don is wonderful

with kids says Godlewski When he explains

firmly what has to be done Sean will giddy up

But he also has a soft touch when its needed

A cleft palate can impair a childs hearing

speaking and eating

Huebener takes time

with parents explaining

what he and other physishy

cians and dentists must

do to correct problems

At each stage hes told

me After this procedure

Sean will get better

and he always does

Godlewski says

Smile Doctor 21

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

Children with serious medical conditions require comshy

plex treatment of which dental care is an important

component Unfortunately it is often the missing comshy

ponent because there are not enough dentists who are

willing and able to tackle the challenges of caring for a

special needs child According to the American Medical

Association dental care is the greatest unmet need of

these children

Lisa Burbes could not find a dentist willing to treat

her infant daughter Hope until Huebener stepped in

Hope had a congenital heart defect which would require

B~IDGI G HE

Complex pediatric medical conditions require the care of multidisciplinary speshycialists and teamwork is crucial notes Donald V Huebener 0OS MS with praise for his School of Medicine colleagues While in general medicine and denHstry have grown up apart and had separate schools of education its fortunate that doctors from both disciplines work together very closely at Childrens he says

The manifold resources at St Louis ChildrenS Hospital and Washington University make them outstanding facilities for the very sick child The Medical Centers Cleft Palate and Craniofacial Deformities Institute which Huebener helped found currently treats more than 2200 cleftshypalate patients as well as some 1800 children with other head deformities The Institute brings together the many specialists needed by these patients including plastic and oral surgeons otolaryngologists speech pathologists audiologists pediatricians pediatric dentists prosthodontists orthoshydontists nurses and team coordinators

Care of cleft-palate patients begins in infancy As a plastic surgeon operates to join the upper lip Huebener professor of plastic and reconstructive surgery and of pediatrics custom-tailors an appliance

22 Smile Doctor

G P BET pound

similar to a retainer Inserted in the roof blood wont clot Huebener explains You of the mouth the appliance helps correctly have to be careful even about giving local mold and contour the palate Further proceshy anesthetics because he may start to bleed dures are performed and other appliances from the needle stick In such cases installed as the child grows sheds baby Huebener has to consult with the childs teeth and gains permanent teeth Care pediatric hematologist about building usually is completed when the up the appropriate coagulation patient reaches the age of factor in the blood before 19 or 20 and Huebener he goes to work and his colleagues Children with mark the occasion psychomotor disturshywith a graduation bances who are ceremony unable to stay still in

Children with the chair may require other health problems sedation or general also require specialized anesthesia and so may care Achild with epilepsy very young children with may have a seizure while extensive caries CerebralOr 06r1 treatsin the dentists chair so palsy patients also find it Huebener must be ready ~15tner ~pp~ difficult to keep still but to prevent him from hurting Huebener has found that(lIst6rnerhimself In addition some by holding their heads drugs children take to control seizures affect the central nervous system so he must be careful about the amount of local anesthetic given for a procedure

For a child with severe hemophilia a loose baby tooth is a potentially dangerous problem If you just pull the tooth the child may start to hemorrhage because the

four surgeries by the time she was 2 years old She also

was prone to cavities Left untreated they could provide

a reservoir for contagion that threatened to spread

Dental caries (tooth decay) is an infectious disease

Huebener professor of pediatrics explains Bacteria may

go through the enamel into the dentin then into the

nerve and enter the bloodstream If a child has a heart

defect the bacteria may lodge there and create problems

Hope now is 9 and has not needed surgery in five

years But she still requires vigilant dental care because

the re-routing of blood flow resulting from surgical COfshy

rection also may make the heart vulnerable to bacteria

Hope doesnt mind the frequent visits She really likes

D

gently he often can work on them without general anesthetic

The complex medical cases he treats provide Huebener and his colleagues with the opportunity to meet unique professional challenges But it is his deft personal touch that allows him to be both doctor and friend to his young patients

Summer 200 I Outlook

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23

I

PtAtiet1(e is tJeir rnidUer1tAme

~d 966d blfdd~ is tl1eir 9tArne

- DONAlD y H UEBENE ~ DDS ~1S

From the exam chair to the goody drawer Huebener keeps his young patients smiling

D r Don Burbes explains as Hope selects her prize

(a ring as usual) His whole staff is good with children

Infection spreading from dental caries also is a threat

to children with other medical problems Before a child

can receive an o rgan transplant surgeons require a clean

bill of oral health from Huebener The drugs that preshy

vent the immune system from rejecting the transplant

also lower the bodys defenses against bacterial infection

Huebeners current patients include three receiving hearts

and one receiving a double-lung transplant along with a

number of children receiving liver and kidney transplal1ts

Cancer patients need meticulous dental care before

and during chemotherapy a treatment that causes their

white blood celJ count to go down thus making them

vulnerable to infection Huebener works closely with their

pediatric oncologists Any dental carc- an extraction

a filling even a rou tine cleaning has to be timed with

chemotherapy he explains

Huebener sympathizes with parents who come to

him after a long day of trudging from one specialists

office to another

Theyre overwhelmed with their childs problems

and now theyre being sent to still another doctor he says

He remembers one mother of a very sick boy who came

Outlook Summer 2001

in feeling exhausted discouraged and hostile He sat

down with her I told her Im here to help you in any

way 1 can Your sons problems are my concern And as

we talked all the negativity went away Now were the

best of friends

Huebener believes in being completely honest with

parents H e spends a lot of time with them explaining

their childs condition and discussing treatment options

Lisa Burbes Hopes mother notes that Huebener has

spoken several times to her support group for families of

children with heart defects

Relationships with families of cleft-palate patients

like Sean Godlewski become especially close because the

course of treatment is long 1 had a 16-year-old in today

whom I first saw as a baby Huebener says Over the

years you become a friend of the family Parents call

frequently seeking advice not just on medical care but on

such issues as whether their child with a cleft deformity

can go out for football or take up a wind instrument

( ETII N( A S T THE f EAIlt Asked the secret of his rapport with his young patients

Huebener smiles and replies Pediatric dentists are also

psychologists Patience is their middle name and good

buddy is their game Contrary to popular belief he

observes fear of the dentist is not a normal part of childshy

hood It arises because all too often parents wait until

children have a mouthful of cavities to take them for

their initial visit Ideally dental visits should begin when

the first baby tooth comes in You build a relationship

of confidence and trust so that when you do have to give

them local anesthesia for a filling its not the end of the

world Huebener says

To put the young patient at ease he talks as he works

explaining what he is going to do and why it is necessary

In this he emulates his own fondly remembered childshy

hood dentist who let him play with the gizmos and

gadgets in the office and who made a dental checkup

an occasion to look forward to His interest sparked

Huebener went on to attend Washington University

School of Dental Medicine The school which closed in

1991 had a fine department of pediatric dentistry says

Huebener and it was the chair Patricia Parsons DDS

who inspired him to make children his lifes work

Theres always something to look forward to says

Huebener something I havent seen before or helped a

patient with Thats what makes my job so fascinating 0

Smile Doctor 23